Altering physical properties of pharmaceutical co-crystals in a systematic manner

Abstract

Systematic structure-property studies on a series of co-crystals of potential cancer drugs with aliphatic dicarboxylic acids were undertaken. This study reveals that systematic changes to the molecular nature of the co-crystallizing agent combined with control over the way individual building blocks are organized within the crystalline lattice makes it possible to establish predictable links between molecular structure and macroscopic physical properties, such as melting behaviour and aqueous solubility. However, it is not possible to find any notable correlation between physical properties-chemical compositions in the absence of structural consistency.

Thermodynamic characteristics of cocrystal formation and melting points for rational design of pharmaceutical two-component systems

“…26 On the other hand, literature data show that there is a linear correlation between the Gibbs energy of sublimation and melting temperatures 27 of structurally similar compounds (classified by Tanimoto similarity coefficients 28 ). 29,30 Unfortunately, as the data about cocrystal melting temperatures is scattered across different works and there is no common data 15 base, there have been no attempts to systematize and analyze these values yet. There are some works dedicated to obtaining the regularities between the melting temperatures of cocrystals and their individual components.…”

Dicarboxylic Acid Separation by Dynamic and Size‐Matched Recognition in Solution and in the Solid State

“…[1,3] Chromatography separation [1] and crystallization from solvent are the most effective methods for separating the acid mixture with low cost and high efficiency,despite the fact that organic solvents are used and alarge amount of mixed binary fractions is still obtained. [5] Furthermore,v arious artificial receptors for dicarboxylic acids were reported, exploiting their strong hydrogen-bond donor ability. [5] Furthermore,v arious artificial receptors for dicarboxylic acids were reported, exploiting their strong hydrogen-bond donor ability.…”

“…By washing with water the obtained powder,f ollowed by filtration, we quantitatively recovered adipic acid with > 80 %p urity (Supporting Information, Section S7.2, Figures S22-S23, Table S13). Similarly, by adding 1,6-diiodododecafluorohexane (4-6)t oas olution containing 1-12 and 2-6,the obtained solid precipitate was the halogen-bonded co-crystal 1-12·4-6,a nd the solution contained exclusively pure suberic acid (2)(3)(4)(5)(6). After adding an equimolar amount of 4-4 to aCHCl 3 /MeOH (9:1) mixture solution containing 1-10 and 2-4,aw hite solid powder immediately precipitated.…”

Dicarboxylic Acid Separation by Dynamic and Size‐Matched Recognition in Solution and in the Solid State

“…[4] Adipic and suberic acids are also extensively used as pharmaceutically acceptable co-crystal formers for crystallizing and improving water solubility of active pharmaceutical ingredients. [5] Furthermore,v arious artificial receptors for dicarboxylic acids were reported, exploiting their strong hydrogen-bond donor ability. [6] In these studies,i tw as shown that the perfect fit of the diacid in ar eceptor cavity is essential for selective recognition.…”

“…Full characterization of the filtered precipitate indicated the quantitative formation of pure halogen-bonded co-crystal 1-10·4-4,w hile the supernatant contained nearly 99 %ofstarting adipic acid. Similarly, by adding 1,6-diiodododecafluorohexane (4-6)t oas olution containing 1-12 and 2-6,the obtained solid precipitate was the halogen-bonded co-crystal 1-12·4-6,a nd the solution contained exclusively pure suberic acid (2)(3)(4)(5)(6). Similar displacements were observed by gas-to-solid exchange reaction experiments,w here dicarboxylic acids 2-4 and 2-6 were completely replaced by the size-matched DIPFAs 4-4 and 4-6 in their complexes with 1-10 and 1-12,r espectively (Supporting Information, Section S8.2).…”