Carbamazepine - Stabilization Against a Hydrate

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 

Phenobarbital is an anticonvulsant in the barbiturate class with sedative and hypnotic effects [78]. In the past, combinations between barbiturates and analgesics were used because barbiturates tend to increase the action of these drags. Phenobarbital has also been co-administered with theophylline to partially offset the increased heart rate associated with the compound. A combination product containing theophylline, phenobarbital and ephedrine HCl is currently in use for the treatment of asthma, emphysema and bronchitis. Several years ago, variation in the performance of the brand name combination product Tedral, marketed by Parke-Davis Canada Inc., compared with generic versions were noted [81]. Over time, and possibly guided by a clinical observation of performance when co-administering a combination of theophylline and phenobarbital, it was 

Theophylline has also been co-crystallized with urea [87] A-(2-ammonioethyl)carba-mate [88], chlorosalicylic acid [89], sulfathiazole, 5-fluorouracil [90], p-nitroaniline [91], succinic acid, malonic acid, maleic acid and oxalic acid [92]. There is evidence that at least one of these co-crystals, between theophylline and oxalic acid, can improve the physical stability of theophylline by protecting it from converting to the less soluble hydrate at high humidities. In this case, oxalic acid and water both hydrogen bond with theophylline at the same site. It is unclear whether or not the occupancy of the hydrogen bonding site by another molecule, in this case oxalic acid prevents the conversion to the hydrate or, if a general decrease in solubility of the oxalic acid co-crystal versus the hydrate is responsible for the protective effects. 

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