Effect of hvdrophilic substances on liberation of quinidine from starch - methylcellulose spheres

The spheres were prepared by the desolvation technique combined with gravitational sedimentation of droplets of methylcellulose gel suspensions with the addition of 25 % quinidine adsorbate on the potato starch and 5 % hydrophilic agents such as Span 80, Tween 60, glyceryl monostearate or PEG 2000 instilled into a desolvation liquid (saturated sodium acetate : paraffin liquid : heptane 1:1:1, vlvlv) through a standardized capillary. As follows from the physicochemical studies the sphericity (Sp) changed within the range 1.020 - 1.314, the porosity (P) was 19.1 - 66.5 % and the loading efficiency was 35.10 - 67.07 %. The release studies show that the dissolution efficiency after 60 min (DEso) in acidic medium was 78.6 % for quinidine and 52.6 - 63.4 % for the spheres; in phosphate buffer pH 6.8 DEm was 32.4 % for quinidine, but ranged within 16.3 - 26.0 % for the spheres. The release of the drug from the spheres was fast and it was slightly difference (the loaded drug was released within 60 min) in acidic medium, while differentation of release in the phosphate buffer made it possible to evaluate the effect of hydrophilic additives on the dissolution rate. The general process of release can be described by the modified Higuchi equation Mi =KO (fi - a) , which facilitates the analysis of the theoretical amount of the released substance (M;) depending on the zero-order dissolution rate constant (KO) and the dissolution lag time (TD). Accordingly, spheres with sustained release can be most effectively produced by addition of PEG 2000. These spheres are characterized by Sp = 1.035, P = 60.2 % and a loading efficiency of quinidine 67.07 %. The release in acidic medium proceeds with KO = 3.857 mg-min0.5 and TD = 6.21 min, in phosphate buffer KO was 1.293 rng.rnir~-'.~ and To = 7.14 min. These parameters were of less importance for the other formulations. The modified Higuchi equation gives information about the parameters of drug released. the effect of hydrophilic substances on the efficiency of loading, and on the kinetics of quinidine gastric

The release of active agents is tested according to pharmacopoeal methods recommended for tablets (BP 93. USP XXII, Eur. Ph. 3rd Edition 1996).
Literature lacks sufficient data on preparing quinidine spheres by the technique of desolvation of suspensions of starchmethylcellulose sorbats into a desolvation liquid. Therefore, the aim of this study was to prepare the spheres by desolvation of concentrated suspensions with different composition and to determine the effect of hydrophilic substances on the efficiency of loading, and on the kinetics of quinidine release in artificial gastric or intestinal fluids.

Results and Discussion
The compositions of spheres are shown in Table 1 Table 1. The formulations of quinidine spheres In aacordance with the formulations given in Table 1, quinidine spheres were prepared using the desolvation and gravitation technique consisting in instilling sticky suspensions into the desolvation medium. The desolvation medium consists of three liquids: the upper layer was heptane, the medium one was paraffin oil, and the lower was a saturated solution of sodium acetate. Droplets falling through the hydrophobic layers were rounded, and next their surface areas became hydrophobic. Then they slowly shifted into the saturated solution of sodium acetate, where the droplets underwent desolvation and were rounded and hardened after 0.5 h. Macroparticles were dried at room temperature and stored in a desiccator over anhydrous calcium chloride. The metod proposed for sphere production is simple, economic and does not require complicated technical equipment. Moreover, homogeneous spherical particles can be obtained using capillaries of standardized outlet. The desolvation liquid can be used many times after the previous saturation of sodium acetate of the liquid. For the production of spheres evaporation, utilization of toxic solvent vapours, and other chemicals harmful for the environment is not necessary. The obtained spheres were evaluated by their physical characteristics. Table 2. Physical characteristics of quinidine spheres The data in Table 2 show that the long axis (L) changed within the range 2.135 -3.000 mm. The sphericity (Sp) was calculated using the equation (34) to some extent on the hydrophilic character of these components. Table 3. Loading efficiency of quinidine spheres (n = 6) The loading efficiency of the active substance (  These values are presented in Tables 4 and 5. Table 4. Liberation kinetics of quinidine from spheres in 0.1 M HCI (n = 6) Qquinidine in substance Table 5. Liberation kinetics of quinidine from spheres in phosphate buffer pH 6.8 (n = 6) The data in Table 4

Preparation of spheres
The quinidine adsorbate and the hydrophilic substances were ground and then suspended in methylcellulose gel. The suspension was stored at 4 '~ for 24 h to improve rheological properties and after warming to room temperature, it was diluted with an appropriate amount of water and dropped from 9 -10 cm height into the desolvation medium consisting of sodium acetate saturated solution, liquid paraffin, nheptane (50 : 50 : 50, v/v/v) through a capillary tube of 0.9 mrn in diameter. The spheres were kept in the desolvation liquid for about 30 min. Then they were filtered, washed with water, dried at room temperature, and stored in a desiccator over anhydrous calcium chloride.

Physical characteristics
The spheres size (mm diameter) and weight (mg) were determined by measuring the long (L) and short (I) axes of 100 sphere units and weighing 100 sphere units (stereoscopic microscope, type MSt 127: with a magnification x 21 Poland, analytical balance type Metter AT 201 Switzerland).
The true density (pt) of spheres was measured by using a pycnometer with ethanol (760 gA) as a dispersion liquid at room temperature.

Drug content
The assay procedure was similar to "Quinidine Sulfate Capsules" in USP XXII.

Release study
The release study was carried out in a miniflowcell apparatus (38)  Each measurement was performed six times for each preparation.