Introduction

Growing expectations and demands regarding drug quality have been stimulating research and development of new pharmaceutical compounds. In the meantime, drug quality does not solely depend on the characteristics of the active principles and on the production process, but also on both the quality and functionality of the excipients utilized. ^1-2 The excipients also influence in a significative fashion the release of the active principle contained in the medicine.^3-4 During the production process, the intrinsic characteristics of the (solid state) excipients as well as of the active principle are reflected in important parameters of the tablets, such as compressibility, fluidity, ability to form uniform mixtures, lubrication, sedimentation and solubility.^5-6 More and more, excipients are gaining increasing prominence within pharmaceutical formulations, assuming now multiple functions critical to the effectiveness, safety and stability of the dosage forms.⁷ Over recent years the pharmaceutical industry has been looking over alternative materials from plant origin possessing high starch content ^5,8-10 that would, on one hand, allow to overcome certain difficulties inherent to the compression process in the production of tablets and, on the other hand, exhibit economic feasibility. The brans of cassava (Manihot esculenta) flour and of cassava starch flour are residues arising from industrial processing of cassava to produce cassava flour and cassava starch flour and are therefore potential candidates for the development of new pharmaceutical materials and excipients to be used in pharmaceutical solid dosage forms aiment at oral administration. These brans possess a large amount of starch in their composition, low levels of impurities, and can be produced in large scale and at a low cost ^5,10,11. Hence, in this research effort the major goal was to characterize both the bran of cassava starch flour (Bsf) and the bran of cassava flour (Bf), and to fully assess their potential as new tablet excipients.

Materials and Methods

Results and Discussion

Venlafaxine hydrochloride is selective serotonin reuptake inhibitor used in the treatment of depression; it was selected as model drug for investigation because Venlafaxine hydrochloride is selective serotonin reuptake inhibitor used in the treatment of depression; it was selected as model drug for investigation because it was selected as model drug for investigation because it was selected as model drug for investigation because

The results of the physicochemical analyses performed to Bsf and Bf cassava bran samples are displayed in Table 2. The results obtained are compatible with the reference values^17-19 except for the lipid and ash contents.

The two cassava bran types possess enough concentrations in starch so that they can be utilized as tablet disintegrants. The observed indices of ash and lipid, above the standards established by USP 30¹⁷ and Cereda ²⁰ were probably due to several factors, namely the source of the raw material (vegetable origin), agronomic practices, milling procedures, and chemical modifications that starch are prone to. The average size of particles obtained in cassava brans Bsf and Bf were determined after sieving because granule shape and granule size determine powder fluidity (Table 3). In general, particles whose size varies between 0.25 mm and 2.0 mm do flow freely. With particles smaller in size than 0.1 mm, flow is a problem in most materials.¹⁴

The results obtained for other physicochemical, characteristics of the cassava bran (Bsf and Bf) granules are displayed in Table 4.

Powders with a low angle at rest, typically close to 25°, do flow freely, while those with high angles at rest, typically higher than 50°, display a bad flow.⁴ A compressibility index (CI) with values smaller than 15% usually reflects an easy outflow of the sample particles, while values higher than 25% indicate a difficult flow of the particles.²¹ Considering the aspects evaluated, the use of particles of Bsf resulting from sieves 40, 50, and 60 is not critical in the performance of the tablet manufacturing process, and all have good flow characteristics, with CI between 13.63 and 16.27 % (Table 4). However, the granules of Bf from sieve 80 may facilitate the manufacturing process due to a better flow of the particles, resulting in tablets with lower resistance to disintegration (CI of 38 %), although being bulkier (d_comp = 0.47 g mL^-1). In spite of the fact that Bf particles resulting from sieve 80 displayed better flow characteristics and less resistance to disintegration, one opted to use the Bf particles from sieve 100, a powder defined as being semi-fine¹². Even though not presenting the best flow, the compacted density with a higher value (d_comp = 0.697 g mL^-1) indicates a more cohesive material, favoring the process of compaction (CI of 61.40%). For the Bsf particles, one opted to use in the pharmaceutical formulation the particles from sieve 50, a powder defined as being moderately coarse¹². In the granulometric distribution of Bsf the higher retention of particles occurred in mesh with size 0.3 mm (sieve 50), while for Bf the higher retention of particles was produced in the mesh with size lower than 150.0 µm. Therefore, the Bsf particle size in sieve 50 was higher than the Bf particle size in sieve with mesh the sizes smaller than 100. This is due to the greater amount of fiber present in Bsf bran, providing a more heterogeneous mixture where the starch is adhered to the fiber. Bsf has better flow characteristics due to both a low cohesion between the particles and their larger size, while Bf presents a worse fluidity due not only to the better cohesion between particles but also to their smaller size.

Experimental tests with cassava brans and with Starch1500^® produced a higher swelling index of Bsf (360 ± 34%) when compared to that of Bf (180 ± 16 %). Starch1500^® presented the highest swelling index (420 ± 5%). Inspite of the differences in the swelling profile, the results obtained in this study indicate that cassava brans possess a high potential as disaggregating agents for pharmaceutical formulations^22,23) Venlafaxine hydrochloride was selected as model drug for this study due to its high aqueous solubility.²⁴ The other components employed in the formulations are commonly employed in the production of tablets.⁴ The tablets of the three formulations produced with higher compression forces (160-200 MPa) resulted in tablets with a better appearance. The results obtained in the physical tests performed are displayed in Table 5. The values of disintegration time of a tablet are related to the processes of dissolution/absorption and, hence, to the bioavailability of the drug, while the hardness and friability of a tablet will define their physical stability.²⁴

The physical tests performed indicated a slightly different behavior for Formulation I, higher hardness and null friability, compared to the other formulations. The tablets from formulation I made with Bf presented a better physical stability, providing them with a better appearance and resistance. The results of the desintegration tests were the same for both forces employed. In all samples, after a time period of 30 min, 100 % of the venlafaxine chlorhydrate was released. One can also infer that, being the disintegration of a tablet an action usually prior to the dissolution process, Bf and Bsf produced a fast disintegration time thus confirming the potential of cassava brans as tablet disintegrants.

Conclusions

Formulation I presented better physical stability, physicochemical and pharmacotechnical characteristics as compared to formulations II and III. The tests performed on the tablets produced using Bsf and Bf cassava brans revealed that these brans exhibit physicochemical characteristics very similar to those presented by Starch1500^®. It can be concluded that the cassava by-products Bf and Bsf could replace with advantage the excipients traditionally used by the pharmaceutical industry to produce tablets.