Formulation and evaluation of immediate release tablets with different types of paroxetine hydrochloride powders prepared by direct compression


The behaviour of the bulk solids is clearly influenced by shape and surface characteristics of the particles integrating a powder (Holgado et al., 1996). The parameters of flowability clearly show that monocrystalline PRX is absolutely inappropriate for direct compression. Angle of repose could not be determined for unmodified PRX because its rheological characteristics were very poor. Prismatic shape of PRX crystals and high surface compression characteristics. In the case of PRX D.C and coated PRX, smaller values of Hausner ratio and Carr’s index theoretically predict better flowability and compressibility. The particle size determination (Table 2) shows that PRX D.C. has the finest particles, which should therefore be able to rearrange in phase of compression and create new surfaces. As a consequence, the tablets will have increased mechanical strength. Furthermore, PRX D.C. has needle shape particles, which increases the specific contact surface area and therefore, compressibility.

The best flow properties were found for coated PRX, which is related to its spherical shape (Figure 1). Particles of coated PRX are very porous and crystals of the active ingredient are implemented inside of the particles. Minimal contact of PRX crystals between coated PRX particles significantly improves flowability and compressibility.

Because of the high content of PRX in the mixture, PRX’s physical characteristics will have an essential influence on the compression properties and elastic relaxation of the tablets. This could be explained with dominant PRX-PRX interactions, which are responsible for more cohesive properties of the mixture and consequently poor flowability. Also, these interactions have an influence on elastic recovery, which has been associated with the storage of elastic energy during compression, as deformation energy under stress, and subsequent release of this energy after removal of axial pressure. On the other hand, spherical structure and protection of PRX crystals inside of coated particles provided compression of higher percentage of active ingredients in comparison to PRX D.C. It was impossible to compress the powder mixture of unmodified PRX with the automatic method on single punch tableting machine because of very high elastic relaxation and capping of the resulting tablets. Furthermore, it was infeasible to make tablets with lactose superdisintegrants (Starlac®, Microcellac®, Ludipress®) and crystalline PRX due to the fact that in these kinds of formulations lactose has limited ability to form strong tablets and it has low dilution potential.

Tablet properties
The mechanical strength of tablets is often defined as the force required fracturing a tablet across its diameter (Martinello et al., 2006). Mechanical strength is directly related to porosity and disintegration time. The packaging process and transportation of the final product requires appropriate tablet strength. Properties of powder mixtures show that PRX D.C. provides greater crushing strength which is in correlation with smaller particle size and higher specific surface area that assures new contact surfaces and bonding between particles. Furthermore, crushing strength of formulations with Polyplasdone® XL- 10 is increased in comparison to formulations containing Vivasol®. The reasons for this are higher compressibility of Polyplasdone® XL-10 (Desai et al., 1994), (unique particle morphology) and the greater content of microcrystalline cellulose - MCC (Avicel PH® 200). Avicel PH® 200 has a nominal mean particle size of 180 _m and because of increased surface area, enables direct compression of mixtures with higher content of PRX than Avicel PH® 101 (Martinello et al., 2006, Rowe et al., 2004). In addition, highly compactable Avicel PH® 200 contributes to greater crushing strength of tablets, which could be explained with the increase in number of mechanical interlocking between MCC particles. Small crushing strength of tablets with coated PRX is associated with particle size, shape and coating of PRX particles. The larger granules with smaller surface area and higher percentage of voids inside of such tablets with consequently weaker inter-particulate bonding requiring the lower crushing strength for diameter fracture (Eichie and Kudehinbu, 2009).
When pharmaceutical powders are compacted into tablets, elastic recovery is responsible for capping, lamination or chipping phenomena. There are different theories to explain capping tendencies, such as entrapment of air, elastic characteristics of materials, radial relaxation of tablets and non-uniform density distribution (Wu et al., 2007).
As mentioned previously, it was not possible to manufacture tablets with unmodified PRX because of the high degree of axial relaxation and tendency for capping. Furthermore, tablets containing modified PRX also showed tendency to cap. Solution for this was usage of Klucell® EXF (hydroxypropylcellulose – HPC) binding agent for direct compression, in concentration of 2% in each formulation. HPC is nonionic, water-soluble cellulose ether with remarkable thermoplastic characteristics, and it has a very high degree of plastic flow. Low molecular weight, low viscosity grades of HPC (EXF) are recommended as immediate release binders. Therefore, when HPC was utilized, it provided toughness, absorbed the compression energy, and finally decreased the ejection force.
Recently, newer classes of natural binders with excellent properties regarding tabletability (stronger interparticulate cohesive bonds) that are also related for manufacturing of tablets with immediate release have been involved (Eichie and Amalime 2007; Ngwuluka et al., 2010; Martins et al., 2007).

Disintegration and dissolution profiles
One of the aims of this paper was also to produce immediate release tablets, which is especially important for treatment of depression. We used PRX, which is classified in Class II, according to the BCS (high permeability, low solubility) (FDA guidelines, 1995). For drugs in Class II, the principal limitation of its oral absorption is its dissolution rate. Because of that, it is necessary to use more than one dissolution medium as a prognostic tool in the assessment of both drug potential for oral absorption and the bioequivalence of its formulation (Dressman et al., 1998). A tablet is considered to be rapidly dissolving when more than 85% of the labeled amount of drug substance (Q + 5%) dissolves within 30 min in a volume of < 900 ml buffer solution using USP Apparatus I or II (United States Pharmacopeia 30th ed., 2007).
To improve disintegration we used superdisintegrants crosscaramellose sodium (Vivasol®) and cros-spovidone (Polyplasdone® XL-10). Effect of disintegrants and PRX powders on disintegration time of tablets was investigated. Obtained results are shown in Figure 3. However, tablets formulated with coated PRX show faster disintegration time than those prepared with PRX D.C. In the case of coated PRX, present superdisintegrants provided approximately the same disintegration time. On the other hand, different results were obtained in case of tablets with PRX D.C. Tablets formulated from PRX D.C. and Polyplasdone® XL-10 are less porous (Table 4) in comparison to tablets from PRX D.C. and Vivasol®. As a consequence, wicking, which is assumed to be the mechanism of action of Polyplasdone® XL -10 is limited by low porosity of tablets. Possible explanation for decreased disintegration and dissolution of tablets with PRX D.C. and Polyplasdone XL-10® is the very high packaging fraction which obstructs the penetration of fluid into the tablet that would cause the matrix of the tablet to break.
The relationship between the wetting time and disintegration time of tablets is shown in Figure 4.
According to this relationship, as soon as the water penetrates the tablet, it disrupts the interparticulate matrix bonds causing the tablet to fall apart. It has also been reported that crosscaramellose absorbs large amount of water and swells (Table 4). It has been reported that disintegration mechanism of Polyplasdone® XL-10 is wicking, and because of this, tablets containing this superdisintegrant expressed delayed disintegration resulting in filling up the tablet voids (Zhao and Augsburger, 2005b). The dissolution study of the market formulation of PRX (500 mg) demonstrated complete drug release within 30 min. All prepared tablets, except the formulation of PRX D.C. and Polyplasdone® XL-10 showed complete drug release within 30 min. According to results obtained by ANOVA, all formulations show statistically significant differences in dissolution profiles for the first 15 min (data not shown). Also, model independent approach that uses difference factor (f1) and similarity factor (f2) was determined to compare dissolution profiles. Results of fit factors were summarized in Table 5. Generally, f1 values up to 15 (0 to 15) and f2 values greater than 50 (50 to 100) guarantied equivalence of the two dissolution curves and furthermore test and reference similarity (Costa et al., 2003). According to fit factors, formulation with PRX D.C. and Polyplasdone® XL-10 is different in comparison to the reference, while other formulations exhibited similarity in dissolution profiles.
Elaboration of how pH affects the efficiency of the superdisintegrants in terms of dissolution is completely different among scientists. It was reported that, when the superdisintegrant was incorporated into the tablet, dissolution within 15 min was slower in the acidic medium than that in the neutral medium regardless of whether crosspovidone or crosscaramellose was used (Gordon et al., 1993). Also it was pointed out that in a capsule formula (PRX + dibasic calcium phosphate + magnesium stearate) the dissolution was faster in 0.1 N HCl than in deionized water due to the dibasic calcium phosphate excipients (Dahl et al., 1991). Furthermore, Chen et al. (1997) reported that interaction between ingredients in tablets with PRX may lead to different dissolution rates, especially in the acidic medium (Chen et al., 1997). Moreover, Zhao and Augsburger (2005a) demonstrated different dissolution rates from lactose and dicalcium phosphate tablets where croscarmellose was used as superdisintegrant in acidic and neutral media. They also established the same behaviour of Polyplasdone® XL-10 in both media. In our experiment, dissolution data from tablets containing PRX D.C. and Polyplasdone® XL-10 were significantly different in all investigated dissolution media and in all time points when compare to other formulations. This result is in correlation with the small porosity of tablets and longer wetting and disintegration time (Murkesh et al., 2007).

*Significance level (p < 0.05).

Fit factors

pH 1.0; t = 5, 10, 15, 20, 25, 30

pH 4.5; t = 5, 10, 15, 20, 25, 30

pH 6.8; t = 5, 10, 15, 20, 25, 30







































Table 5. Fit Factors, I-Paroxetine D.C. + Polyplasdone XL-10®; II-Paroxetine D.C. + Vivasol®; III -Paroxetine coated + Polyplasdone XL-10®; IV- Paroxetine coated + Vivasol®; V-Reference.

Percentage of dissolved active principle from tablets with PRX D.C. and Polyplasdone® XL-10 did not vary significantly in acidic and neutral media in all time points. This was also confirmed for formulation with coated PRX and Polyplasdone® XL-10, which also verify that behaviour of Polyplasdone® XL-10 is not dependent of pH (Buckton, 1990). Mild agitation force exerted by dissolution paddles (50 rpm) was not strong enough to cause complete breakdown of the larger fragments of tablet that resulted in smaller percentage of dissolved drug in comparison to tablets with Vivasol®. Na Zhao and L. L. Augsburger also confirmed this fact (Zhao and Augsburger, 2005a).
On the other hand, percentage of dissolved active principle from tablets with Vivasol® was greater in acidic medium than in neutral (Figure 5). This result was not expected, because of the decrease swelling capacity of Vivasol® in acidic medium (Zhao and Augsburger, 2005b). Possible explanation for this is the formation of a gel layer in neutral pH, which presents a depot of PRX. However, this result is desired in case of immediate release tablets, which are intended to disintegrate in the stomach, and provide a fast effect. Statistically different percentage of dissolved PRX between tablets with Vivasol® is evident only in the first 5 min in pH = 4.5 and pH = 6.8 (Figure 2b, 2d). It is obvious that dissolution of drug in pH = 6.8 is delayed. This is in correlation with greater swelling and gelling capacity of crosscaramellose in neutral pH (Figure 2d)
Considering the results, best disintegration time and dissolution profile were obtained for coated PRX. Production of tablets with coated PRX is less variable, which is confirmed by appropriate flow of its powder, uniform mass of tablets, improved friability, and disintergration time. Furthermore, presented superdisintegrants provide approximately the same disintergration of prepared tablets. These results confirm positive effect of coating of PRX particles on manufacturing of tablets with immediate release.

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