Abstract

Background: Atenolol is a commonly used antihypertensive drug of class III BCS category. It suffers from the problem of poor intestinal absorption or permeability thus low bioavailability. The objective of the present study was to enhance the permeability of atenolol by using a suitable technique, which is economical and devoid of using any organic solvent.

Methods: The nanocrystal technology by high-pressure homogenization was chosen for this purpose, which is a less expensive and simple method. In this technique, no organic solvent was used. The study was further aimed to characterize prepared nanocrystals in the solid state by Fourier Transform Infrared Spectroscopy (FTIR), Powder X-Ray Diffraction (PXRD) patterns, particle size, zeta potential, %yield and drug permeation study through isolated goat’s intestine. An in-vivo study was carried out to determine the pharmacokinetic property in comparison to pure drug powder using rats as experimental animals. The formulation design was optimized by a 3(2) factorial design. In these designs, two factors namely surfactant amount (X1) and speed of homogenizer (X2) were evaluated on three dependent variables namely particle size (y1), zeta potential (y2) and production yield (y3).

Results: PXRD study indicated the presence of high crystal content in the prepared formulation. These nanocrystal formulations were found with a narrow size range from 125 nm to 652 nm and positive zeta potential of 16-18 mV. Optimized formulations showed almost 90% production yield. Permeability study revealed 90.88% drug release for optimized formulation in comparison to the pure drug (31.22%). The FTIR study also exposed that there was no disturbance in the principal peaks of the pure drug atenolol. This confirmed the integrity of the pure drug and its compatibility with the excipients used. A significant increase in the area under the concentration-time curve Cpmax and MRT for nanocrystals was observed in comparison to the pure drug. The higher values of the determination coefficient (R2) of all three parameters indicated the goodness of fit of the 3(2) factorial model. The factorial analysis also revealed that speed of homogenizer had a bigger effect on particle size (-0.2812), zeta potential (-0.0004) and production yield (0.0192) whereas amount of surfactant had a lesser effect on production yield (-370.4401), zeta potential (-43.3651) as well as particle size (-6169.2601).

Conclusion: It is concluded that the selected method of nanocrystal formation and its further optimization by factorial design was effective to increase the solubility, as well as permeability of atenolol. Further, the systematic approach of factorial design provides rational evaluation and prediction of nanocrystals formulation on the selected limited number of smart experimentation.

Keywords: Atenolol, nanocrystal, factorial design, ANOVA, antihypertensive, pharmacokinetic.

Graphical Abstract