Evaluation and comparison of dissolution data derived from different modified release dosage forms: an alternative method.
ABSTRACT Dissolution testing is an essential requirement for the development, establishment of in vitro dissolution and in vivo performance (IVIVR), registration and quality control of solid oral dosage forms. The objective of the present study was to investigate the effect of delivery system positioning in accordance with the USP 23-recommended dissolution methods and the proposed modification on drug release from controlled release systems having different operating release mechanisms, namely, swellable floatable, swellable sticking and osmotic pump. The delivery systems were evaluated by placing each dosage form either in the dissolution vessel in accordance with the USP 23 methods or over/below a designed ring/mesh device for achieving full surface exposure to the dissolution medium for sticking or floatable systems respectively. Results indicate that the overall release profiles from the sticking and floatable systems of theophylline are sensitive to their positioning in the dissolution vessel (P<0.05). Furthermore, release of diltiazem hydrochloride from the sticking system also demonstrated sensitivity (P<0.05). In contrast, the floatable dosage form of this latter drug with the application of a helical wire sinker, or when it was placed below the ring/mesh assembly, or by allowing the dosage form to float, did not show sensitivity (P>0.05) for the overall release behavior. This was attributed to the greater solubility of diltiazem hydrochloride (50% solubility in water at 25 degreesC) in comparison to theophylline which is a sparingly soluble drug (0.85% solubility in water at 25 degreesC). Drug release from the osmotic pump appeared to be identical under the given experimental conditions (P>0.05). Statistical analysis of data was performed by comparing the t50%, t70%, t90%; mean dissolution times (MDT50%, MDT70%, MDT90%); the "difference factor, f1" and "similarity factor, f2". It is concluded that the results derived from the application of the "similarity factor, f2" are superior to the individual time points (e.g. tx%) and MDTx% values in differentiating between overall release patterns or the border line release profile differences. It also became apparent that in the case of the swellable sticking systems full surface exposure to the dissolution medium results in greater release rate. For the osmotic pump the required osmotic pressure threshold necessary for constant rate drug delivery appears to have reached independent of the hydrodynamic conditions. A successful and more accurate evaluation of dissolution data can be derived when full surface exposure is considered and this can be accomplished by dissolution method modification with the aid of the designed ring/mesh assembly.
- [show abstract] [hide abstract]
ABSTRACT: The purpose of this study was to develop a new ternary polymeric matrix system that is easy to manufacture and that delivers a highly soluble drug over long periods of time. Pectin, hydroxypropylmethylcellulose (HPMC), and diltiazem HCl granulated with gelatin at optimized ratios were blended at different loading doses and directly compressed. Swelling behavior, dissolution profiles and the effect of hydrodynamic stress on release kinetics were evaluated. Diltiazem release kinetics from the ternary polymeric system was dependent on the different swelling behavior of the polymers and varied with the drug loading dose and hydrodynamic conditions. Drug release followed either non-Fickian or Case II transport kinetics. The relative influence of diffusion and relaxational/dissolution effects on release profiles for different drug loadings was calculated by a nonlinear regression approach. Photographs taken during swelling show that the anisotropic nature of the gel structure, drug loading dose, swelling capacity of polymers used, and the design of delivery system all play important roles in controlling the drug release and dissolution/erosion processes. Zero-order delivery of diltiazem HCl from a simple tablet matrix was achieved. The ternary polymeric system developed in this study is suitable for controlled release of highly soluble drugs. It offers a number of advantages over existing systems, including ease of manufacturing and of release modulation, as well as reproducibility of release profiles under well defined hydrodynamic conditions. Our delivery system has the potential to fully release its drug content in a controlled manner over a long time period and to dissolve completely.Pharmaceutical Research 11/1997; 14(10):1415-21. · 4.74 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The dissolution rates for hydrocortisone alcohol and acetate were determined using a stationary disk/rotating fluid system. The hydrocortisone was compressed in a tablet die, and the die placed in a vessel above a rotating magnetic bar. Dissolution rates were evaluated in aqueous media under conditions involving the following independent variables: solubility (Cs), diffusion coefficient (D), viscosity (v), rotational speed (omega), and tablet radius (r). A design equation which relates dissolution rate (R) to these variables was formulated for the system R alpha Cs D2/3 (v) -1/6(omega)1/2(r)3/2 This design equation adequately represents the system, which is related to fluid mechanics and convective diffusion models. The fluid mechanics model assumes that the fluid ideally rotates as solid-body rotation and the momentum layer is initiated at the outside radius of the tablet die. The convective diffusion model is based on the formation of a diffusion layer at the outside radius of the dissolving surface and a predictable relationship between the momentum and the mass transport quantities of bulk viscosity and diffusion coefficient. This configuration, like the rotating disk in a stationary fluid, offers the attractive attribute of being useful to study drug release mechanisms for systems of pharmaceutical interest.Pharmaceutical Research 09/1988; 5(8):495-500. · 4.74 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The objectives of this work were to apply several profile comparison approaches to dissolution data of four different but bioequivalent metoprolol tartrate tablet formulations to (1) identify the advantages and disadvantages of each approach, (2) quantify the metric for comparing dissolution profiles of each method, (3) determine metric limits that are consistent with the observed bioequivalence, and (4) rationalize the observed metric limits with respect to the role of dissolution in overall metoprolol absorption. Dissolution was performed by the USP monograph method on four formulations of metoprolol tartrate tablets (Lopressor plus fast, medium, and slow dissolving test formulations). Three general approaches to compare dissolution profiles were examined; they were ANOVA-based, model-independent, and model-dependent approaches. It is concluded that model-independent approaches and several model-dependent approaches yielded numerical results that can serve as objective and quantitative metrics for comparing entire dissolution profiles of the four metoprolol tartrate formulations. However, these methods presented complications. Some metrics were dependent on the length of the dissolution profile and the sampling scheme. Results from the pairwise procedures also depended on the pairing assignment of individual profiles. In spite of complications, these methods suggested wide dissolution specification limits. Wide dissolution specifications were rationalized through an analysis of in vitro-in vivo relationships, which indicated metoprolol dissolution from these formulations was not the rate-limiting step; hence, a range of dissolution profiles can be expected to yield equivalent plasma profiles.Journal of Pharmaceutical Sciences 07/1997; 86(6):690-700. · 3.13 Impact Factor