Dissolution Of Diazepam Research Articles

Comparison of Different Liquid and Semisolid Vehicles Selected for Oral Administration of Pellets and Minitablets with Diazepam: In Vitro Investigation

The acceptability and palatability of a dosage form are extremely important to improve patient compliance. Mixing oral solid dosage forms with food carriers is often necessary to ease swallowing and provide the taste-masking effect. The present research investigated how a liquid or semisolid carrier influences the disintegration time and drug dissolution rate of pellets and minitablets with diazepam. The disintegration of pellets and minitablets in liquid carriers (water, milk and apple juice) was determined using a texture analyser. Dissolution tests were performed for the dosage forms dispersed in gel vehicles (2% carmellose and 0.5% carbomer gels) or applesauce. The disintegration of minitablets in water and apple juice was fast (1 min), but it slowed to 3 and 5 min in milk and gel vehicles, respectively. The pellets disintegrated in liquid carriers within 3 min. The drug dissolution rate in 0.1 M HCl depended on the gel viscosity in this medium. The preserved high viscosity of a carmellose gel inhibited the dissolution of diazepam. On the other hand, the viscosity of the carbomer gel decreased rapidly, and in effect, the dissolution rate of diazepam from the incorporated pellets or minitablets was comparable to the dissolution from loose pellets or minitablets.Graphical abstract

Influence of the carrier on the intrinsic rate of dissolution of diazepam in interactive mixtures.

The use of interactive mixtures of drugs adhering to the surface of carriers can promote drug dissolution. The mechanism of dissolution of such mixtures has been studied using the rotating-disc method under conditions eliminating secondary influences such as carrier surface characteristics and drug particle aggregation. Levich plots were used to characterize the dissolution behaviour. Diazepam-compactrol interactive mixtures had initial dissolution rates similar to that of pure diazepam owing to the deposition of a continuous layer of diazepam on the disc surface from the interactive mixture. Linear Levich plots were produced at all drug loadings and the presence of compactrol in the disc slightly enhanced dissolution rates. Dissolution rates for diazepam-emcompress interactive mixtures were lower than those of pure diazepam. The Levich plots for these systems were non-linear with increasing negative curvature as the diazepam loading decreased. The rate of dissolution of diazepam in the lactose interactive mixture was markedly higher than that of pure diazepam, but high diazepam loadings in the lactose mixtures inhibited diazepam dissolution. Rapid carrier dissolution caused surface retraction of the disc, enhancing the dissolution rate. The Levich plots showed an upward curvature due to turbulence. Linear Levich plots for diazepam and other benzodiazepines and for diazepam-compactrol interactive mixtures showed that their dissolution in pH 5 phosphate buffer was diffusion-controlled. The Levich plots for diazepam-emcompress interactive mixtures were indicative of some interfacial control during dissolution, but the hypothesis of common ion precipitation of dissolved carrier, calcium phosphate, onto the disc surface did not fully explain this effect.

Impact of Particles Size Distribution on Diazepam 5mg Tablets Dissolution

Diazepam is one of most frequently prescribed benzodiazepines. It is classified as a class I substance according to the Biopharmaceutics Classification Scheme (BCS). Diazepam tablets were prepared using different API rawmaterials. Before the formulation, we measured particle size distribution on Malvern Instruments Ltd Mastersizer 2000. The tablets were prepared by employing conventional wet granulation. The formulations were evaluated for hardness, friability, content uniformity, in vitro disintegration time (DT), release profiles. The dissolution profile testing is performed on the two formulations with different particles size distribution. Test parameters were: medium 0.1 mol / l hydrochloric acid, 900 ml, temperature 37°C ± 0.5°C, Mixing Speed 100 rpm, Number of tested tablets 12, Testing Cycle 10, 15, 20, 25 and 30 min. Instrument: Varian Van Kel VK7025, Varian Cary 50. We used the spectrophotometric method with absorbance measuring on 242 nm for quantification. Results for particle size distribution for first Diazepam API particle distribution were d (0.10): 88.743 μm; d (0.50): 305.231 μm; d (0.90): 655.911 μm, and for the second raw-material of API was d (0.10):1.998 μm; d (0.50): 4.419 μm; d (0.90): 8.845 μm. The results of diazepam dissolution for two formulations and f2 value with reference drug are presented in Table 1:

Modelling the dissolution of diazepam in lactose interactive mixtures

The dissolution of diazepam (1–10%) in lactose interactive mixtures was studied using the USP paddle method over rotational speeds of 50–200 rpm to elucidate the mechanism of dissolution and to model the process. Dissolution of diazepam was concentration dependent and occurred rapidly, i.e., greater than 95% dissolved within 10 and 20 min for the 1 and 10% mixtures, respectively. Conventional dissolution models like the Hixson-Crowell Cube Root Law, Wagner's log probability plot and monoexponential equations provided unsuccessful data fits. The hypothesis that dissolution occurred from both dispersed and aggregated particles was tested using a biexponential model. Data treatment using the Marquardt-Levenberg non-linear least squares algorithm (Peakfit®) provided good fits. The rate constants for diazepam dissolution from the dispersed and aggregated particles and their initial concentrations were estimated and was consistent with the observed concentration-dependent behaviour. Laser diffraction was used to demonstrate the existence of dispersed particles and aggregates during the dissolution process. Studies in surfactant solution provided further indirect evidence of aggregate formation.

The Solid Dispersion of Benzodiazepins with Phosphatidylcholine. The Effect of Substituents of Benzodiazepins on the Formation of Solid Dispersions.

Solid dispersions of four benzodiazepins, nitrazepam (NZP), nimetazepam (NMP), diazepam (DZP) and medazepam (MZP), with phosphatidylcholine (PC) were prepared to investigate the effect of functional groups of benzodiazepins. These benzodiazepins were present in an amorphous state immediately after preparation of the solid dispersion. The limit mole fractions for the amorphous state were 0.50 (NZP), 0.25 (NMP), 0.25-0.40 (DZP) and 0.25 (MZP). Infrared spectra and thermal analysis suggested an interaction, probably a hydrogen bond, between PC and NZP. In contrast, no interaction was suggested between PC and NMP, DZP or MZP, because they have no functional donor groups for the hydrogen bond. NZP solid dispersion showed no change after 1 year, but NMP, DZP and MZP solid dispersion showed recrystallization of drugs after 1 year. Thus, it was considered that some interaction between PC and the drug was needed to prevent the recrystallization. Dissolution of NZP in pH 7.0 phosphate buffer solution was much faster from NZP solid dispersion than from NZP crystals, and there was no aging effect of the solid dispersion. Dissolution of DZP also improved with the formation of a solid dispersion, but the dissolution rate became slower with time.