Co-crystal Hydrates

The addition of a liquid to a grinding mixture of two co-crystal components can sometimes enable co-crystallisation through the formation of a product that incorporates the molecules of the liquid as a constituent. For this reason, grinding in the presence of liquids is a versatile technique for searching for three-component co-crystals e.g. co-crystal hydrates, inclusion compounds ). In some... 

The same co-crystal hydrate is also obtained by the neat grinding of theophylline hydrate with anhydrous dtric add, the neat grinding of anhydrous theophylline with dtric acid monohydrate, as well as the neat grinding of theophylline monohydrate with dtric add monohydrate. Neat grinding of anhydrous theophylline and anhydrous dtric acid, by contrast, leads to the formation of an anhydrous co-crystal of 1 1 stoichiometry (Figure 8.18(c)). The similarity of the supramolecular motifs within the co-crystal hydrate to those observed in theophylline monohydrate and citric acid monohydrate crystals (Figure 8.19) suggests that, in the presence of water, the co-crystal hydrate could... 

Figure 8.19 Similar structural motifs between (a) a co-crystal hydrate of theophylline and citric acid, (b) citric acid monohydrate and (c) theophylline monohydrate. ...

Figure 11.14 Phase diagrams for theophylline-citric acid (THP-CTA) anhydrous and co-crystal hydrate in water at 25 °C. Eutectic points are indicated by (THP hydrate/THP-CTA hydrate), Ej (THP-CTA hydrate/THP-CTA anhydrous) and Ej, (THP-CTA anhydrous and CTA hydrate). Solubilities of THP hydrate and CTA hydrate are indicated by a and b in each plot. (a) Phase solubility diagram generated from measured eutectic points and models that describe co-crystal solubility behavior, (b) Schematic triangular phase diagram showing the stability domains for anhydrous and hydrated co-crystals with co-formers that modulate the water activity. Stability regions for the crystalline phases are 1, crystalline drug hydrate 2, co-crystal hydrate 3 anhydrous co-crystal 4, co-former hydrate 5, crystalline drug hydrate/co-crystal hydrate 6, anhydrous/hydrated cocrystals 7, anhydrous co-crystal/hydrated co-former.

A. Jayasankar, L. Roy and N. Rodriguez-Hornedo, Transformation pathways of co-crystal hydrates when coformer modulates water activity, J. Pharm. Sci., 2010, 99, 3977-3985. 

There are other soUd states which sometimes confuse the measurement and definition of solubiUty. The dmg may crystaUize as a hydrate, i.e. under inclusion of water molecules. If the hydrate form is more stable than the pure form it may be difficult to measure the intrinsic solubility of the drug at all. Often drugs tend to precipitate in an amorphous form, often under the inclusion of impurities. As with metastable polymorphs, such amorphous precipitates may lead to erroneously high solubility measurements. CommerciaUy, drugs are often crystallized in salt form, e.g. as the hydrochloride salt, a cation with a chloride anion. In these co-crystallized salts, a much lower solubility than the intrinsic solubility will typi-... 

Radon forms a series of clathrate compounds (inclusion compounds) similar to those of argon, krypton, and xenon. These can be prepared by mixing trace amounts of radon with macro amounts of host substances and allowing the mixtures to crystallize. No chemical bonds are formed the radon is merely trapped in the lattice of surrounding atoms it therefore escapes when the host crystal melts or dissolves. Compounds prepared in this manner include radon hydrate, Rn 6H20 (Nikitin, 1936) radon-phenol clathrate, Rn 3C H 0H (Nikitin and Kovalskaya, 1952) radon-p-chlorophenol clathrate, Rn 3p-ClC H 0H (Nikitin and Ioffe, 1952) and radon-p-cresol clathrate, Rn bp-CH C H OH (Trofimov and Kazankin, 1966). Radon has also been reported to co-crystallize with sulfur dioxide, carbon dioxide, hydrogen chloride, and hydrogen sulfide (Nikitin, 1939). 

In a solid-gas reaction involving a molecular crystal, the reactants are respectively the molecules in the crystalUne solid and the molecules in the gas phase and the product is the product crystal, which can be crystalUne or amorphous. Vapour uptake to generate a solvate crystal (e.g. hydration) is a related process. In fact the difference between a crystal solvation process and a solid-gas reaction leading to new molecular/ionic species is mainly in the energetic scale of the processes and in the fact that in solvation processes, molecules retain their chemical identity. On this premise there is a relevant analogy between the uptake of smaU molecules by a nanoporous material [16] and the reaction between a molecular crystal and molecules to yield a co-crystal or a salt (e.g. acid-base... 

It is also possible to have the chirality associated with a non-SHG active counterion, while the harmonic generating unit is non-chiral, e.g. formate ion co-crystallized with chiral amines. Often, such crystals will also incorporate one or more waters of hydration, depending on the conditions of crystallization. Finally, other chiral structures, such as those shown in Figure 5 could be utilized. It is clear that a wide variety of such crystals are possible, and that harmonic generating units which are much larger and more nonlinear than the ones we have listed could be used at the expense of a smaller transparency range, when the application warrants it. 

Clathrate hydrates are inclusion compounds formed by the enclosure of a small guest molecule within a hydrogen bonded cage of solid-state water. Clathrate hydrates are co-crystals and are thus distinct from ice, which is made of pure water, and hence can have different physical properties to ice such as a different melting point. The classic example of a clathrate hydrate is the burning snowball of methane clathrate hydrate. The combustion of the methane in the clathrate is self-sustaining, Figure 7.1. Many... 

The observation of Z > 1 may be regarded as a special case of co-crystallisation where the two components are the same as one another. Thus research on high Z structures is closely related to co-crystals, solvates, hydrates etc. Figure 8.48 shows the X-ray crystal structure of a remarkable... 

The structure of the laminarabiose hemihydrate [LAMBIO] is particularly interesting in this respect because it involves the co-crystallization in equal proportions of an anhydrous and monohydrate disaccharide. This structure is really a 1 1 complex between an anhydrous and monohydrate structure with different, but separate, hydrogen-bonding schemes for the anhydrous and hydrated molecules (see Fig. 13.51). 

Compounds of pharmaceutical interest can exist in different solid forms. Broadly, they can be classified as being in the amorphous or in the crystalline state. In crystalline pharmaceuticals, solvates are formed when the solvent molecule is incorporated, either stoichiometrically or non-stoichiometrically, in the crystalline lattice. Hydrates are a subclass of solvates, wherein the incorporated solvent is water. Because of regulatory considerations, non-aqueous solvates find limited use as pharmaceuticals. Our dis-cu.ssions will, therefore, be restricted to hydrates. If the solvent is non-volatile, co-crystals are obtained, and this is an emerging field in solid-state pharmaceutics. In case of weakly acidic and basic compounds, salt forms are prepared with the goal of obtaining the desired biopharmaceutical properties. Figure 3 is a schematic representation of the various types of solid forms of interest in pharmaceuticals (6). 

Co-crystals are made from reactants that are solids at ambient conditions [66], Therefore all hydrates and other solvates are excluded which, in principle, eliminates compounds that are typically classified as clathrates or inclusion compounds (where the guest is a solvent or a gas molecule). 

Crystalline amino acids form readily hydrates, salts and various molecular complexes and co-crystals. The molecular conformations, the hydrogen bond geometric parameters and patterns, dipole moments and the charge distributions can be tuned finely in these systems, and many structure-forming units and structural patterns... 

FIGURE 9.20 The cations [c/s-Ni(phen)2CI(H20)]+ and [c/s-Ni(phen)2(H20)2]2+ co-crystallize with three PFg" counterions and HjO solvate molecules (not shown). If the counterions were Cl , these would be hydrate isomers. (Molecular structure drawing created from CIF data, with hydrogen atoms omitted for clarity.)... 

A study of the relaxational transitions and related heat capacity anomalies for galactose and fructose has been described which employs calorimetric methods. The kinetics of solution oxidation of L-ascorbic acid have been studied using an isothermal microcalorimeter. Differential scanning calorimetry (DSC) has been used to measure solid state co-crystallization of sugar alcohols (xylitol, o-sorbitol and D-mannitol), and the thermal behaviour of anticoagulant heparins. Thermal measurements indicate a role for the structural transition from hydrated P-CD to dehydrated P-CD. Calorimetry was used to establish thermodynamic parameters for (1 1) complexation equilibrium of citric acid and P-CD in water. Several thermal techniques were used to study the decomposition of p-CD inclusion complexes of ferrocene and derivatives. DSC and derivative thermogravimetric measurements have been reported for crystalline cytidine and deoxycytidine. Heats of formation have been determined for a-D-glucose esters and compared with semiempirical quantum mechanical calculations. ... 

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