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

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


Flowability
Flowability was defined according to Hausner ratio:

Hausner ratio = (Tapped density) / (Bulkdensity)            (3)

Flow of powder was measured using a standard funnel as described in Ph. Eur. VI (European Pharmacopeia, 2008). Into a dry funnel, whose bottom opening has been blocked by suitable means, a test sample was introduced without compacting. After unblocking the bottom opening of the funnel, the time needed for the entire sample to flow out thought the funnel was measured.

Angle of repose
Angle of repose was determined by measuring the height of the cone of powder and calculating the angle of repose - α, from the given equation (Equation 4). The end of a funnel was placed 2 cm above a flat base. The funnel was filled with the powder (the used mass depended on the bulk density of the material, around 2.5 g), therefore after releasing the powder out of the funnel the top of the resulting cone reached the end of the funnel. From the height of the cone (h) and the diameter at the base (d), the angle of repose, (α) was determined.

                                 (4)         

Compressibility index

Compressibility index was determined according to Carr’s index:

               (5)    

Table 1. Direct compression formulation.

Ingredients

Formulation I

Formulation II

Formulation III

Formulation IV

PRX D.C. 

30

30

-

-

PRX coated 

-

-

40

40

Kolidon VA

4

4

2

2

Vivasol©

-

5

-

5

Polyplasdone® XL

4

-

4

-

Avicel PH 200 

12.5

11.5

8.64

7.64

Klucel EXF

2

2

2

2

Peg 4000 

1

1

1

1

Mg-stearate 

1

1

1

1

Aerosil 200 

0.5

0.5

0.5

0.5

Dry sieve analysis
Particle size distributions of PRX bulk powders, and powder mixtures were determined using a stack of metal sieve plates from the largest to the finest aperture in the following order: 500, 355 (Der Shuenn, Taiwan), 250, 180, 125, 63 and 45 μm (Cole-Palmer, Illinois). Retsch apparatus type AS 200 basic was used for the analysis (F.Kurt Retsch GmbH and Co KG, Germany). The weight of the powders retained on the surface of each sieve plate was divided by the total sample weight to obtain the corresponding weight percentage oversize for each sieve fraction.

Morphology of powder
The scanning electron microscope (Supra 32 VP, Zeiss, Germany) was used to observe the morphology of the PRX powders.

Preparation of tablets
The formulations of PRX tablets are presented in Table 1. Drug and excipients without the lubricants were first mixed for 30 min. Magnesium stearate and Aerosil® 200 are sieved through a sieve (180 μm) and after adding them into the mixture, the mixing was continued for 5 min. Finally, the powder mixture was sieved (sieve 500 μm). Tablets of 55 mg in weight and 4 mm in diameter were prepared by direct compression using a single-punch tableting machine, Kilian SP 300 (Kilian and Co GmbH, Germany). Tablets were compressed with force of 9 kN and compression speed of 25 tbl/min. Finally, the weight and diameter of tablets were measured.

Tablet properties

Uniformity of mass, tablet hardness and friability
The average tablet weight was determined by weighing 20 tablets individually using an analytical balance (European Pharmacopeia, 2008).
Hardness was determined using tablet hardness tester (Vanderkamp VK 200, VanKel Industries, Inc., Edison, NJ, USA). Ten tablets of each formulation were tested. Friability was determined by placing 10 tablets of each formulation in a TAR 10 friabilator (Erweka GmbH, Heusnstamm, Germany) and operating the drum for 4 min and 25 rpm. Friability was determined using the following formula:

Friability = [(Initial weight-Final weight) / Initial weight)] x100 [%]          (6)

Measurement of tablet porosity

Tablet porosity (ε) is calculated using Equation 7

ε = 1 - ρat       (7)    And

ρ = m/2r2h

where ε is the porosity,  ρa  is the apparent density, ρt  is the true density, m is the mass, r the radius, and h the height of the tablet. The diameter and thickness were determined with a thickness meter (Digitale Schiebelehre, Mister Tool, Walter Werkzeuge Salzburg GmbH, Austria).

Wetting time

The wetting time of tablet was measured by the method described by Bi et al. (1996). The method is as follows. A piece of tissue paper (12 × 10.75 cm) folded twice was placed in a small culture dish, and the time for complete wetting was measured at 25ºC. The wetted tablet was then weighed. Water absorption ratio, R was determined according to the following equation:

                    R = Wb-Wa
                             Wa                                 (8)

Where, Wa and Wb are the weight before and after water absorption, respectively.

Disintegration time
Disintegration time was measured with Erweka apparatus Type ZT4 -1, disintegration tester (ERWEKA GmbH, Heusnstamm, Germany). Tests were carried out in 800 ml of distilled water at 37 ± 0.5°C. All tests were run using six tablets of each formulation.

Dissolution study
Dissolution profiles were determined using the paddle method described in USP XXX (United States Pharmacopeia 30th ed., 2007), and the paddle speed of 50 rpm/min (VanKel VK 7000; VanKel industries Inc, Edison, NJ, USA). Dissolution was tested in buffer solutions pH = 1.0 (0.1 N HCl), pH = 4.5 (phosphate buffer), pH = 5.8 (phosphate buffer) and pH = 6.8 (phosphate buffer). The volume of the dissolution medium was 900 ml at 37.0 ± 0.5°C and was prepared according to the Eur. Ph VI. Samples of 10 ml were withdrawn from the dissolution medium at appropriate time intervals and filtered through a membrane filter (pore size 0.45 µm). Each experiment was carried out using six tablets. The samples were appropriately diluted (50×) in a fresh quantity of the dissolution medium. The absorbance was measured by a spectrophotometer (UV-Visible Spectrophotometer 8643, Agilent, France) at 243 nm.

RESULTS

Bulk powder properties
The active ingredients tested in this paper exhibited considerable differences in their powder properties. As shown in Table 2, Hausner ratio, Carr’s index and flow were significantly higher for monocrystalline PRX in comparison to PRX D.C. and coated PRX.

Properties of powder mixtures
Modifications of PRX powder improved the flowability andcompressibility, according to the results presented in Table 3.

Tablet properties
The results of tablet properties are summarized in Table 4. It is apparent that the best tablet characteristics have formulations with coated PRX when compared to formulation with PRX D.C. The maximum official weight variation for tablets heavier than 250 mg is 5%, therefore, all formulations met criteria of the Eur. Ph VI specification (European Pharmacopeia, 2008). Furthermore, all formulations met the specification of Eur. Ph VI (European Pharmacopeia, 2008) for friability of uncoated tablets. Regarding the results, investigated formulations demonstrated a statistically significant decrease of friability in comparison to the reference (p < 0.05) (Table 4).

Table 2. Bulk powder properties.

Ingredients

Mean particle size

Bulk density (g/ml)

Flow (s)

Angle of repose

Hausner ratio

Carr’s index

PRX Cryst

>355

0.382

59.9

  ∞

1.90

47.44

PRX D.C.

>45

0.679

35

41.63

1.39

28.12

PRX coated

>250

0.469

30

39.52

1.14

12.36

Table 3. Properties of powder mixtures.

Ingredients

Mean particle

size (μm)

Bulk density

(g/ml)

Flow (s)

Angle of

Repose

Hausner

Ratio

Carr’s index

PRX D.C.+Polyplasdone XL-10

>45

0.479

7.5

40.20

1.31

23.56

PRX D.C.+Vivasol

>45

0.483

8.5

41.63

1.29

22.94

PRX coated+Polyplasdone XL-10

>250

0.609

8.5

39.34

1.29

18.75

PRX coated+Vivasol

>250

0.608

5.2

39.36

1.25

20.00

Table 4. Tablet properties.

Ingredients

Weight (g)

Porosity

(%)

Crushing

strength (N)

Friability (%)

Wetting time

(s)

Water/absorption

ratio

PRX D.C.+Polyplasdone XL-10

0.0559±1.84

15.45

53.19

0.52

742

0.285

PRX D.C.+Vivasol

0.0525±0.43

59.43

50.46

0.51

195

0.402

PRX coated + Polyplasdone XL-10

0.0512±0.03

59.23

71.99

0.24

140

0.479

PRX coated + Vivasol

0.0562±0.52

59.42

65.30

0.24

158

0.755

Reference

0.0551±0.10

-

61.30

0.91

178

0.897

Disintegration time and dissolution profiles
The times required for complete disintegration in water (37ºC, 800 ml) are acceptable according to Eur. Ph VI foruncoated tablets (European Pharmacopeia, 2008) for allinvestigated formulations. Dissolution experimentsperformed on six samples from each formulation aresummarized in Figure 2 (a, b, c, d). According to the results, all formulations met the BCS specification for immediate release dosage forms.

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