Pure Carbamazepine Research Articles

Performance comparison of a co-crystal of carbamazepine with marketed product

The carbamazepine: saccharin co-crystal ( 1) was studied in terms of a series of attributes, including suitability for multi-gram scale-up, propensity for crystal polymorphism, physical stability, in vitro dissolution and oral bioavailability, with the goal of comparing 1 with the marketed form of carbamazepine (Tegretol ®). Preparation of 1 was achieved on a 30 g scale with a conventional cooling crystallization process from alcohol solution without seeding. The compound is not overtly polymorphic. This finding is in contrast to the form diversity of pure carbamazepine, which has four known polymorphs and a host of solvates, including a dihydrate, which is the stable form in the presence of water. Physical and chemical stability of the co-crystal is also shown to be quantitatively similar to the pure drug in the marketed product (Tegretol ®). Finally, comparison of oral bioavailability of 1 with Tegretol ® tablets in dogs shows the co-crystal to be a viable alternative to the anhydrous polymorph in formulated solid oral products. The balance of properties and performance of 1 as a model co-crystal is discussed.

Effect of n-scCO 2 on crystalline to amorphous conversion of carbamazepine

A number of studies have been carried out to investigate the crystalline to amorphous conversion of carbamazepine (CBZ) using solid dispersion techniques. In this study we have tried to achieve conversion using a novel technique combining near-supercritical carbon dioxide (n-scCO 2) and pharmaceutically acceptable polymers (Na CMC and PVP) of varying molecular weights. Physical mixtures were prepared in two identical sets, one exposed to n-scCO 2 treatment and other was untreated. The treated physical mixtures were compared to untreated using PXRD, DSC and USP in vitro dissolution techniques. Routinely used PXRD analysis involves qualitative estimation of the amorphous conversion of a drug. In this work a previously developed mathematical parameter, ratio of ratios (ROR), was utilized to better quantify the crystalline to amorphous conversion of CBZ. The findings from the three methods indicated that only the lowest molecular weight PVP, PVP10k, facilitated significant crystalline to amorphous conversion of CBZ. In vitro dissolution, which is considered as an estimate of bioavailability demonstrated an initial dissolution of CBZ significantly greater in the treated physical mixtures of PVP10k:CBZ than the initial dissolution of the corresponding untreated physical mixtures and pure untreated CBZ.

Solid dispersion of carbamazepine in PVP K30 by conventional solvent evaporation and supercritical methods

This study compares the physicochemical properties of carbamazepine (CBZ) solid dispersions prepared by either a conventional solvent evaporation versus a supercritical fluid process. Solid dispersions of carbamazepine in polyvinylpyrrolidone (PVP) K30 with either Gelucire 44/14 or Vitamin E TPGS, NF ( d-α-tocopheryl polyethylene glycol 1000 succinate) were prepared and characterized by intrinsic dissolution, differential scanning calorimetry, powder X-ray diffraction and Fourier transform infrared spectroscopy. CBZ/PVP K30 and CBZ/PVP K30/TPGS solid dispersions showed increased dissolution rate. The best intrinsic dissolution rate (IDR) was obtained for supercritically processed CBZ/PVP K30 that was four-fold higher than pure CBZ. Thermograms of various solid dispersions did not show the melting peak of CBZ, indicating that CBZ was in amorphous form inside the carrier system. This was further confirmed by X-ray diffraction studies. Infrared spectroscopic studies showed interaction between CBZ and PVP K30 in solid dispersions. The amorphous state of CBZ coupled with presence of interaction between drug and PVP K30 suggests fewer, if any, stability problems. Because the supercritical-based process produced solid dispersions with IDR better than conventional solid dispersions augmented with amphiphilic carriers, stability issues associated with lipid carriers do not apply, which, in turn, implies easier scale up under current Good Manufacturing Practice for this technique.

Influence of polyethylene glycol and povidone on the polymorphic transformation and solubility of carbamazepine

Purpose: Influence of polymers on the polymorphic transition of drugs has received limited attention in the literature. The main objective of this study was to gain an understanding of the influence of polyethylene glycol and povidone on the crystalline modification and subsequently the solubility of carbamazepine in solid dispersions. Methods: The physical state of the drug within the dispersions was determined using DSC and powder X-ray diffractometer. DSC and optical microscopy was used to study the kinetics and morphology of dihydrate formation, respectively. Results: Both the polymeric dispersions showed an improved dissolution profile for carbamazepine. Carbamazepine was present in an amorphous form within the povidone dispersions. In contrast, the PEG dispersions showed the presence of crystalline drug. Higher ratios of drug/PEG resulted in the metastable form I of carbamazepine. Dihydrate formation from both the polymeric dispersions was higher compared with pure carbamazepine. The physical state of the drug and the amount of drug in solution accounted for the higher dihydrate formation from these dispersions. Conclusions: Knowledge of the factors contributing to enhanced solubility is critical to the stability of solid dispersions. Additionally, influence of polymers like povidone on the crystalline transitions of polymorphic drugs may be crucial during its use as a binder in granulation.

In vitro and in vivo evaluation of carbamazepine-PEG 6000 solid dispersions

The present work extended previous physico-chemical investigations on the effects of solid dispersion on the solubility, the dissolution rate and the pharmacokinetic profile of carbamazepine. Solubility studies showed a linear increase in carbamazepine solubility with the increase of PEG 6000 concentration. There is no marked difference between physical mixtures and solid dispersions for the enhancement of carbamazepine solubility by PEG 6000. Less than 60% of pure carbamazepine was dissolved in 90 min. Physical mixtures (carbamazepine phase III) and solid dispersions (carbamazepine phase II) dissolution rates were higher in comparison of the parent drug. The dissolution of carbamazepine phase III was more pronounced than that evoked by the phase II. The dissolution profiles indicated that the percentage of the drug dissolved was dependent on the proportion of PEG 6000. In solid dispersions there was a remarkable enhancement in the dissolution rates of the drug in the vicinity of the eutectic composition as compared with those of corresponding physical mixtures. Hence, the optimum value for the solid dispersion was 80.5±1.7% of carbamazepine having dissolved within the first 10 min compared to 40±1% for the corresponding physical mixtures of the same composition. Statistical analysis of pharmacokinetic parameters confirmed that the carbamazepine:PEG 6000 binary systems displayed higher bioavailability of the drug than the pure carbamazepine. The area under the curve (AUC) values highlighted the evidence that only slight differences in the bioavailability of the drug occur between physical mixtures and solid dispersions prepared at the 80:20 and 50:50 drug:carrier compositions. However, the mean normalized plasma concentrations showed that standard error deviations are rather wide intervals for pure drug and physical mixtures in comparison to solid dispersions. One additional interesting point to consider is the disappearance of the multiple peaks on the individual kinetic curves of the 50:50 solid dispersion composition. Furthermore, our investigations have highlighted the interest of solid dispersions prepared at «near»-eutectic composition as our preliminary data show that the plasma concentration (C 5h) of the drug for the 15:85 dispersed sample containing 150 mg of carbamazepine is not significantly different from that obtained for the 50:50 dispersed sample containing 300 mg of the drug.

Development of carbamazepine:phospholipid solid dispersion formulations

This study is concerned with the development of a carbamazepine (CBZ):phospholipid (PL) solid dispersion formulation with improved dissolution characteristics. CBZ powders were blended with PL to produce CBZ:PL physical mixtures or made into solid dispersions with PL by the solvent method. CBZ exhibited significantly improved dissolution rates in PL coprecipitate (coppt) as compared to the physical mixtures or CBZ alone. Dissolution studies suggested that less than 10:1 ratio of CBZ to PL (9.1% PL) was required to disperse amorphous CBZ completely in the carrier. The coppt yielded a 3.6-fold greater initial dissolution rate (computed over the 5 min of dissolution) than the pure CBZ. Also, the total amount dissolved after 60 min was 2.1-fold greater at a CBZ:dimyristoylphosphatidylglycerol (DMPG) of 10:1 ratio (9.1% DMPG) than for the corresponding pure drug. Increasing the DMPG concentration to 4:1 (20% DMPG) compositions resulted in only a further 10% increase in the initial dissolution rate and 8.5% increase in the limiting concentration. Thus, a small amount of PL improved the dissolution of CBZ to a significant level. Some effect was also observed by changing the composition of the PLs. The coppts were formulated into tablets in order to compare the dissolution profile with that of Tegretol R, a commercially available tablet of CBZ. It was found that the total amount dissolved after 60 min was two-fold higher in our tablet formulation than the commercial product, Tegretol R. Powder X-ray diffraction spectra showed no changes in the diffraction patterns of CBZ in the coppt. It is concluded that CBZ:PL solid dispersions may have clinical advantages of quick in-vivo release to yield better bioavailability than existing commercial formulations.

In Vitro Recovery of Carbamazepine from Ensure

The in vitro recovery of three different dosage forms of carbamazepine (CBZ) when dispersed in gastric or intestinal fluids, in the presence or absence of Ensure was determined. An equivalent of 1 mg of pure CBZ from Tegretol 200 mg of conventional tablets, chewtablets of Tegretol 200-mg and Apo-carbamazepine (200-mg tablets) were dispersed in five dissolution mediums (0.5 ml of Ensure; 0.5 ml of Ensure and 1.0 ml of gastric fluid; 1.0 ml of gastric fluid; 0.5 ml of Ensure and 1.0 ml of intestinal fluid; and 1.0 ml intestinal fluid) and mixed for 1 hr and filtered. The filtrates were then assayed for CBZ using a UV spectrophotometer. The mean recoveries of CBZ for all dosage forms in the various dissolution mediums were: Ensure/gastric fluid, 85%; gastric fluid, 75%, Ensure/intestinal fluid, 59%; intestinal fluid, 79%; and Ensure, 58%. The differences in CBZ recovery from gastric or intestinal fluid, in the presence or absence of Ensure were found to be statistically significant (p less than 0.05). The difference in dosage forms were statistically not discernible. The significant differences observed in recoveries of CBZ due to Ensure warrants an in vivo study to realize the clinical implication of administering CBZ with Ensure.