Cocrystal dissolution rates

Cocrystal products were obtained from the interaction of exemestane with maleic acid, and from the interaction of megestrol acetate with saccharin [70]. While both cocrystal products exhibited improved initial dissolution rates relative to those of respective initial reactants, the rationale for the dissolution enhancement varied. For the exemestane-maleic acid cocrystal, the formation of fine particles explained the observed enhancement in dissolution rate. On the other hand, for the megestrol acetate-saccharin cocrystal produce, the dissolution enhancement was attributed to maintenance of the cocrystal form and its rapid dissolution. 

Dissolution rates of various API cocrystals have been reported. The intrinsic dissolution rates of CBZ NCT and CBZ SAC cocrystals in water are 1.7 and 2.3 times that of CBZ(D) and close to that of the single component anhydrous CBZ(III).f ... 

Childs et al. formulated crystalline complexes with a salt form of an API with carboxylic acids. The antidepressant, fluoxetine hydrochloride, was cocrystallized with benzoic acid, succinic acid, and fumaric acid where the chloride ion acts as a hydrogen bond acceptor for the carboxylic acid groups of the three ligands. Intrinsic dissolution studies were carried out at 10°C because at 25°C, the rates were so rapid that the dissolution rates of the cocrystals could not be distinguished from one another. The fumaric acid 2 1 complex had a similar dissolution rate to that of the crystalline fluoxetine hydrochloride, but the dissolution rate for the benzoic acid 1 1 complex was half that of fluoxetine hydrochloride. Fluoxetine hydrochloride succinic acid 2 1 complex had approximately three times higher dissolution rate, but the dissolution was so fast that an accurate value was difficult to measure. ... 

Non-stoichiometric concentrations and supersaturation with respect to cocrystal can also be generated by solid phases of reactants with different dissolution rates. This is shown in the diagram in Fig. 21. Different rates of dissolution are achieved by different solubilities or by different surface areas of solid reactants. 

One of the main reasons to investigate co-crystals is to increase the solubility of a poorly soluble compound (BCS Class 2 and 4). For neutral molecules, cocrystals can certainly expand the solid forms possible for development, while for a free acid or free base, both salts and co-crystals can be used to improve the solubility profile. There are a number of considerations when discussing solubility data. The first is equilibrium versus kinetic (or apparent) solubility measurements. Kinetic solubility values are approximate values usually based on one measurement at one time point. Unless preliminary experiments have been performed, it is not known if equilibrium has been reached in the time frame used. For equilibrium solubility, a number of time points and measurements are taken to ensure that the solution has reached equilibrium as evidenced by a plateau in the concentration data. This is sometimes called powder dissolution. The time required to reach the equilibrium solubility can also be a factor in development based on the residence time in the stomach and intestines. It is desirable for the drug to dissolve while it is in the gastrointestinal tract and very long dissolution times may result in less absorption of the drug. Powder dissolution rates can also be dependent on particle size therefore the intrinsic dissolution rate may be a better assessment of this parameter. 

Examples of co-crystals having improved solubility and dissolution rates are found in the work of Remenar et al. published in 2003. In this publication Remenar demonstrated that some of the 1,4 dicarboxylic acid co-crystals of cis-itraconazole have solubilities and dissolution rates equal to those of the amorphous form of cw-itraconazole in the commercial formulation which is much higher than those of the crystalline free base. In another example Trask et al. describes an oxalic acid co-crystal of theophylline with improved physical stabilityAnhydrous theophylline exposed for 3 days to 75% relative humidity (RH) will convert to its monohydrated form, the anhydrous oxalic acid cocrystal remains stable even at 98% RH. 

The most useful aspect is that pharmaceutical cocrystals can be attempted to optimize the physicochemical properties of drugs such as solubility, dissolution rate, stability, tableting, and so on, without the need for covalent modification [127,128]. 

Chemkuvada S, Babu NJ, Nangia A (2011) Nitrofurantoin-p-aminobenzoic acid cocrystal hydration stability and dissolution rate studies. J Pharm Sci 100 3233... 

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