Investigation of variability of primary materials on the intrinsic dissolution behavior of carbamazepine

Abstract

Carbamazepine (CBZ) is a poorly water soluble drug, classified as class II according to the Biopharmaceutics Classification System and exhibits at least four polymorphic forms and a dihydrate. CBZ polymorphs have different crystal structures and exhibit different melting points, chemical reactivity, solubility and compactibility, all of which can contribute to the differences in their bioavailability. In aqueous solution, CBZ anhydrous has ability to convert to dihydrate form, and the kinetic of that conversion is important for the dissolution of the drug. Commercially available raw material can contain a mixture of CBZ polymorphs as well as amorphous parts. The aim of the present study was to investigate the effect of the variability of different commercially available CBZ samples on the intrinsic dissolution behavior in order to recommend a strategy to maintain product quality by monitoring the variability of critical parameters of the bulk drug. Therefore, extensive physical characterization of nine anhydrous CBZ samples from three different sources was carried out. Polymorphism (by X-ray powder diffraction XRPD and Fourier transformation infrared - FTIR microspectroscopy), thermal behavior (by differential scanning calorimetry - DSC, hot stage microscopy - HSM), particle size/particle size distribution, morphology, and solubility were investigated. The results showed that the commercial anhydrous CBZ samples exhibited the same polymorphic form, but different morphology, particle size and size distribution, which led to a variation in the kinetics of conversion from anhydrous to the dihydrate form of CBZ and therefore to variation in the kinetics of solubility. The detected variability was suggested to be attributed to variations in the manufacturing processes, such as the use of different solvents in the crystallization stage and/or grinding of the crystals in the final stage of the manufacture of CBZ. Furthermore, disc intrinsic dissolution rate (DIDR) tests of the CBZ samples were conducted in the order to investigate if the DIDR test can provide information about the kinetics of conversion of anhydrous CBZ to its dihydrate form. For that purpose, compacts of pure raw material were prepared using Zwick material tester. The compacts were imbedded in paraffin leaving only one side free to be exposed to the dissolution media. CBZ anhydrous samples showed different intrinsic dissolution behavior. Moreover examined compacts within one sample have shown high standard deviation. Intrinsic dissolution parameters were determined with scope to calculate the transition point of anhydrous to dihydrate conversion for each sample, which was found to vary among the CBZs obtained from different sources between 15 and 25 minutes. Carbamazepine dihydrate samples were crystallized from anhydrous samples in order to be tested on intrinsic dissolution behavior and were characterized by XRPD and DSC to confirm complete dihydrate formation. It was found that all previously detected variations between the different samples were significantly reduced, and all nine samples had constant characteristics. When dihydrate samples were investigated on intrinsic dissolution behavior, the results showed that deviation within one group of samples were reduced and the variations between dihydrates prepared from anhydrous CBZ from different sources did not exist anymore. Considering that excipients can influence phase transformation of CBZ anhydrous to its dihydrate form, binary mixtures of CBZ (from different sources) and Fast Flo® lactose were investigated in this study. Mixtures with different ratios of drug and excipient were compacted to the same porosity, and disintegration time and intrinsic dissolution behavior of the produced compacts were studied. The results showed that the selected excipient had no influence on the anhydrate dihydrate conversion. As a final step in this study, it was proposed to examine if the results obtained for the transition point of anhydrous form to dihydrate can be used to predict the dissolution behavior of CBZ in model formulation. For this purpose, formulations of CBZ were prepared by direct compaction process using different CBZs and Ludipress®, which were subsequently analyzed for disintegration time and dissolution. It turned out that the amount of CBZ dissolved after 15 minutes showed the same order (CBZ B > CBZ A > CBZ P) being identical to the time event of the transition point determined by intrinsic dissolution test, meaning CBZ B had the earliest and CBZ P the latest transition point. Therefore, the intrinsic dissolution test turned out to be a valuable and simple monitoring tool for characterization of CBZ raw materials, to detect the variability of primary material, to be employed for the determination of the transition point and to be used for estimation of CBZ dissolution behavior.