Carbamazepine cocrystals nicotinamide

Fig. 6 Molecular interactions in carbamazepine cocrystals and solvates (A) dihydrate, (B) acetone solvate, (C) carbamazepine saccharin, (D) carbamazepine nicotinamide, (E) carbamazepine acetic acid, and (F) carbamazepine trimesic acid. (Reproduced from Ref...

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. 

Contents 1. Introduction 373 2. Screening for and Preparation of Cocrystal Systems 375 3. Cocrystal Systems Having Pharmaceutical Interest 377 3.1. Cocrystal systems formed by carbamazepine- type molecules 378 3.2. Cocrystal systems formed by nicotinamide with carboxylic acids 380 3.3. Cocrystal systems formed by caffeine and theophylline 382 3.4. Cocrystal systems formed by saccharin 384 3.5. Cocrystal systems formed by carboxylic acids 385 References 386... 

Using the carbamazepine-nicotinamide cocrystal system, a mathematical model has been developed to predict the solubility of cocrystals [41], The model predicted that the solubility of a solid cocrystal is determined by the solubility products of the reactant species and solution complexa-tion constants that could be obtained from the performance of solubility studies. In addition, graphical methods were developed to use the dependence of cocrystal solubility on ligand concentration for evaluation of the stoichiometry of the solution-phase complexes that are the precursor to the crystalline cocrystal itself. It was proposed that the dependence of cocrystal solubility on solubility product and complexation constants would aid in the design of screening protocols, and would provide guidance for systems where crystallization of the cocrystal did not take place. 

The carbamazepine-nicotinamide cocrystal system has been used to illustrate a mechanism for the formation of cocrystals, for which nucle-ation and growth of solid products are determined by the combination of the reactant components to reduce the solubility of the intermolecular complex that eventually becomes crystallized [42], The principles were studied through the use of in situ monitoring of the cocrystallization process in solutions, suspensions, slurries, and wet solid phases of the... 

It was observed that needle-like crystals of the metastable Form-II of the carbamazepine-isonicotinamide cocrystal formed when the ingredients were initially dissolved in ethanol, but that over time plate-like crystals of the stable Form-I grew in the suspension [44]. It was concluded that the molecular packing in Form-II consisted of carbamazepine dimers hydrogen-bonded to nicotinamide chains, and where the pyridine nitrogen of isonicotinamide did not participate in the hydrogen bonding. 

K. Seefeldt, J. Miller, F. Alvarez-Nunez, N. Rodriguez-Hornedo, Crystallization pathways and kinetics of carbamazepine-nicotinamide cocrystals from the amorphous state by in situ thermomicroscopy, spectroscopy, and calorimetry studies, J. Pharm. Sci. 96 (2007) 1147-1158. 

N. Chieng, M. Hubert, D. Saville, T. Rades, J. Aaltonen, Formation kinetics and stability of carbamazepine—nicotinamide cocrystals prepared by mechanical activation, Cryst. Growth Des. 9 (2009) 2377-2386. 

The melting points of carbamazepine nicotinamide (CBZ NCT) and carbamazepine saccharin (CBZ SAC) cocrystals lie in between the melting points of the pure component phases. ° CBZ NCT melts at... 

Seefeldt, K. Miller, J. Ding, S. Rodn guez-Hornedo, N. Crystallization of carbamazepine-nicotinamide cocrystal from the amorphous phase. AAPS J. 2004, 6, R6172. 

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