Carbamazepine co-crystal

The relationship between. Keu and a, for carbamazepine co-crystals in aqueous solutions with different pH values and in several organie solvents is shown in Figure 11.16. The data points represent. Keu values and solubilities obtained from measured eutectic solution concentrations of eo-crystal components according to equations (11.40) and (11.42). Co-crystal stoichiometric solubilities increase relative to drug solubility as the [eo-former]eu increases relative to the [drugjeu- Other eo-crystal stoichiometries and solution equilibria are presented in the original publication. ... 

Habgood, M., Deij, M. A., Mazurek, J., Price, S. L., and ter Horst, J. H. 2010. Carbamazepine co-crystallization with pyridine carboxamides Rationalization by complementary phase diagrams and crystal energy landscapes. Cryst. Growth Des. 10 903. 

Finally, carbamazepine tetracarboxylic acid-adamantane [115] represents one of the few examples of clearly defined and predictable 3-D motif observed in a hydrogen-bond-based binary co-crystal. 

Figure 8.46 (a) Amide supramolecular homo- and heterosynthons found in co-crystals of carbamazepine (8.42) and (b) X-ray crystal structure of the carbamazepine-saccharin co-crystal. ... 

The real-time in situ synchrotron PXRD technique found its next application in the mechanistic study of mechanochemically promoted co-crystallization of carbamazepine and nicotinamide as representatives of active pharmaceutical ingredients (API) [62], In the case of carbamazepine saccharin co-crystal, in situ analysis confirmed previous studies by cryomiUing that neat grinding led to amorphization while LAG synthesis rapidly produced the co-crystal. The other investigated system involved two-step neat grinding synthesis of nicotinamide suberic acid 2 1 co-crystal. The ex situ PXRD analysis had revealed a stepwise mechanism with the 1 1 cocrystal as the intermediate. Whereas LAG synthesis was too fast for ex situ approach, in situ monitoring enabled the discovery of an unknown phase that preceded the rapid formation of the 1 1 intermediate (Fig. 1.28). However, the authors were not successful at full characterization of the new phase due to its pronounced instability. 

Form diversity Carbamazepine Polymorph/solvate formation leading to low solubility form Pharmaceutical salts or co-crystals that are less prone to form conversion... 

Figure 3.8 (a) Packing diagram of carbamazepine.formic acid solvate and (b) packing diagram of carbamazepine acetylsalicylic acid co-crystal... 

It has been shown that a saccharin co-crystal of carbamazepine is stable against formation of the dihydrate in water slurry for several days. In addition, only one form of the co-crystal was found during extensive screening [72]. In a small probe study the pharmacokinetics performance of the carbamazepine saccharin co-crystal was found to be similar to that of the marketed immediate release product, Tegretol , but there was some indication that the variability in Cmax and AUC were reduced. 

While much of the literature descriptions of the crystal structures of various carbamazepine forms have focused on differences in hydrogen bonding, it is possible that saccharin disrupts the tt-stacking observed in the anhydrous forms and the dihydrate inhibiting the precipitation of those forms from solution. In this case the co-crystal former, saccharin, may also act as a very effective crystal growth inhibitor for certain, less... 

Figure 3.14 Packing diagram of the carbamazepine saccharin co-crystal and rotated version to emphasize the it-stacking...

M. Hickey, M. Peterson, L. Scoppettuolo, S. Morrisette, A. Vetter, H. Guzman, J. Remenar, Z. Zhang, M. Tawa, S. Haley, M. Zaworotko, and O. Almarsson, Performance comparison of a co-crystal of carbamazepine with marketed product, Eur. J. Pharm. Biopharm., 67, 112-119 (2007). 

Co-crystals of nicotinamide and iso-nicotinamide have been prepared with carbamazepine and formamide, respectively [15]. In these co-crystals it is observed that the homo-dimeric synthon I of amides is always favoured despite there being several other possible hydrogen bonding synthons (Figure 7.10). The homodimers thus formed interact with each other via hydrogen bonding synthon II. 

Figure 7.10 Hydrogen bonding patterns in the co-crystals of two amide derivatives (a) niocotinamide and carbamazepine and (b) iso-nicotinamide and formamide...

Novel techniques for the creation of co-crystals and solvates such as neat and liquid assisted grinding have challenged the ability of crystal structure prediction to predict stoichiometry from first principles. Recent work has addressed the problem of predicting solvate stoichiometry of acetic acid (the solvent) with various molecules including carbamazepine (CBZ) and its 10,11-dihydro derivative (DHCBZ), urea and theobromine(see Figure 4.8). 

Another, more recent example by Rodriguez-Hornedo and co-workers elegantly displayed how micellar additives, such as surfactants, can bring thermodynamic stability to unstable co-crystal phases. An incongruently dissolving carbamazepine salicyclic acid co-crystal was tested and it was found that by introducing various concentrations of aqueous solutions of sodium lauryl sulfate (surfactant), a congruently saturated system resulted. 

Figure 6.4 Form I and Form n of the 1 1 carbamazepine saccharin co-crystal with the hydrogen bonds represented as black, dashed lines.

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