Carbamazepine: saccharin

Two different of supramolecular synthons have been detected in the two polymorphs of the carbamazepine-saccharin cocrystal system [45]. In the Form-I structure, the carbamazepine molecules formed a homo-synthon, with the saccharine molecules also forming a hydrogen-bonded homodimer. The interaction of these two synthons resulted in formation of a one-dimensional array of molecules in a crinkled tape motif. In the Form-II structure, a heterosynthon is formed by the interaction of a carbamazepine and a saccharin molecule. This latter synthon packs in one-dimensional chains that extended along the crystallographic c-axis. 

For pharmaceutical scientists, the value in cocrystals would be if such materials would be superior active pharmaceutical ingredients relative to the drug substance itself. This possibility has been studied for the carbamazepine-saccharin cocrystal, where its performance characteristics were compared with the marketed form of carbamazepine [46]. It was learned that the physical and chemical stability of formulations containing the carbamazepine-saccharin cocrystal product were similar to those of carbamazepine in the marketed product, and comparative bioavailability studies demonstrated that the cocrystal was a viable alternative drug substance to the anhydrous drug form used in the conventional solid dose forms. 

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... 

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...

Studies with other cocrystalline systems are underway, in an effort to confirm the general applicability of these principles, mechanisms, and cocrystallization methods presented here. Transformation to cocrystal from single-component solid reactants has also been observed for sulfadimidine anthranilic acid and sulfadimidine salicylic acid from acetonitrile, ethanol, and water and carbamazepine saccharin from water and O.IN HCl. 

Fig. 26 Effect of reactant crystal form CBZ (anhydrous III) and CBZ (dihydrate) on carbamazepine saccharin (CBZ SAC) cocrystal formation during grinding for 10 minutes under ambient conditions (A) CBZ(D) and SAC before grinding (B) CBZ(D) and SAC after grinding (C) CBZ(III) and SAC before grinding (D) CBZ(III) and SAC after grinding and (E) CBZ SAC cocrystal prepared from solvent. (Adapted from Jayasankar, A. Somwangthanaroj, A. Shao, Z.J. Rodriguez-Hornedo, N. Cocrystal formation during cogrinding and storage is mediated by amorphous phase. Pharm. Res. 2006.)...

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. 

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. 

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

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.

Figure 11.2 Co-crystal solubility of carbamazepine-glutaric acid (CBZ-GTA), car-bamazepine-nicotinamide (CBZ NCT), carbamazepine salicylic acid (CBZ-SLC), carbamazepine oxalic add (CBZ-OXA), carbamazepine-saccharin (CBZ-SAC) and carbamazepine succinic acid (CBZ-SUC) as a function of melting temperature in isopropyl alcohol (X), ethanol (open square), ethyl acetate (open triangle) and water (filled circle). Adapted with permission from Good and N. Rodriguez-Homedo, ref. 20. Copyright 2009 American Chemical Sodety.

Theophylline saccharin 1 1. Indomethacin saccharin 1 1. Carbamazepine saccharin 1 1. Megestrol saccharin 1 1. 4-Methylpyridin A -oxide saccharin 1 1. Ethenzamide saccharin 1 1. ... 

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