Caffeine co-crystals

Structure determination from PXRD data has been regarded as an invaluable tool to elucidate the structures of active pharmaceutical ingredient (API) co-crystals [41]. Trask et al. described the mechanochemical synthesis of several caffeine co-crystal... 

Polymorph control by solvent-drop grinding during co-crystallization of caffeine with glutaric acid. 

Another example of a computational study of co-crystal stability is given by the work on caffeine (see Figure 4.4) co-crystallising with monohydroxybenzoic acids (HBA) (see Figure 4.6). Experimentallyit is found that 2-HBA and 3-HBA form 1 1 co-crystals with caffeine, while 4-HBA forms a concomitant mixture of 1 2 and 2 1 co-crystals. 

The ability to vary the nature of the liquid phase in LAG allows control over the polymorphic behaviour of mechanochemically obtained co-crystals. This was demonstrated by Trask et al. in mechanochemical co-crystallisation of caffeine with glutaric acid. Co-crystallisation of the two components in chloroform solution provided the co-crystal (caffeine)-(glutaric acid) as two concomitant polymorphs. However, LAG with either chloroform or cyclohexane resulted in the selective formation of each form separately (Figure 8.6(a)).This control of polymorphic behaviour was also observed in LAG screening for co-crystals of piroxicam." The application of LAG to the control of polymorphism is not limited to co-crystals, however and has also been shown to be applicable to single-components systems, for example anthranilic acid (Figure 8.6(b)). ... 

An attractive aspect of co-crystallisation in the synthesis of new API forms is the possibility of forming co-crystals containing identical constituents in different stoichiometric ratios.Mechanochemical methods provide a particularly simple procedure for constructing such stoichiometric variations by simply grinding different amounts of starting materials. This was first demonstrated for the model API caffeine upon co-crystallisation with acetic... 

Figure 8.7 (a) Mechanochemical synthesis of the co-crystals (caffeine)-(acetic acid) and (caflFeine)-(acetic acid)2 and (b) schematic structures of hydrogen-bonded chains in the 1 1 and 2 1 co-crystals of terminal dicarboxylic acids with the model API nicotinamide ... 

The use of co-crystals to enhance the hydration stability of a solid API was first demonstrated for model APIs caffeine and theophylline by forming cocrystals with dicarboxylic acids. Co-crystallisation with oxalic, malonic, maleic and glutaric adds provided co-crystals based on the expected carboxylic acid-imidazole " heterosynthon. In both cases, the co-crystal with oxalic acid demonstrated enhanced hydration stability compared to the solid APIs and did not transform into a hydrate even after seven weeks exposure to 98% relative humidity. Similar observations were also made in the case of analogous co-crystals of theophylline. ... 

Second Case Study Heterothermal Co-crystallization in Caffeine I Glutaric Acidj Acetonitrile System (from Yu et... 

A complete phase diagram of the system caffeine, glutaric add and acetonitrile was constructed from 10 to 35 °C (see Figure 9.8(a)). Batch runs were carried out in a thermostatted stirred vessel. A saturated solution with respect to the caffeine/glutaric acid co-crystal solid phase was prepared at 35 °C. The solution was cooled down to 34 °C to be slightly supersaturated. Seeding with cocrystals was then performed in order to avoid uncontrolled primary nucleation. 

K. Guo, G. Sadiq, C. Seaton, R. Davey and Q. Yin, Co-crystallization in the caffeine/maleic acid system lessons from phase equilibria, Cryst. Growth Des., 2010, 10, 268-273. 

Examples of co-crystals Carbamazepine oxalic acid 2 1. Caffeine oxalic acid 2 1. ... 

In yet another example, a co-crystal of caffeine and adipic add [98] has been isolated by a co-crystallization methods based on a suspension/slurry containing both components of the co-crystal system. This approach provides an optimal environment for the putative co-crystal formation because the activity values of both... 

Imidazole and Related Donors. Structural models for the co-ordination geometries of a Cu-Cu" redox couple in copper enzymes suggest a mechanism for where both electrons and protons are involved a model has been characterized bis(imidazole) copper(ii) diacetate (102). Dark green crystals of [Cu(caffeine)Cl2,H20] in which copper is tetragonal pyramidal distorted towards trigonal bipyramidal have been characterized Cu—Ni = 1.98 A,Cu—0(H20) = 1.96 A, Cu—Cl = 2.32,2.25 A. Dinitrato-2,6-bis-[l-(phenylimino)ethyl]pyridinecopper(ii) (103) contains a planar... 

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