1. Formulation, Characterization of Pellets of Duloxetine Hydrochloride by Extrusion and Spheronization
Prof. V. R. Sinha
University Institute of Pharmaceutical Sciences, Center for Advanced Studies, Panjab University, Chandigarh
INDIA

2. Objective
The objective of the present investigation was to prepare and characterize pellets of Duloxetine hydrochloride by using the technique of extrusion- spheronization.

3. Pelletization
Agglomeration process that converts fine powders of bulk drugs & excipients into small, free-flowing units referred to as pellets.

4. Rationale for pelletization
Flexibility in dosage form design & development
Improve the safety & efficacy of bioactive agents
Disperse freely in the g.i.t.
Reduce variation in gastric emptying rates
Reduce the inter- & intra-subject variability
Avoid High local concentrations
Contd…

5. Controlled release pellets an be manufactured
Pellets have a low surface area-to-volume ratio & provide an ideal shape for the application of film coating
Reproducible & uniform fill weights in capsules
Pellets can be made aesthetically appealing
Average transit time of pellets in the intestine can be increased
Pellets are less susceptible to dose dumping

6. Duloxetine Hydrochloride
Categorized as an antidepressants as dual inhibitor of serotonin and nor-epinephrine reuptake
The clinical indications of the drug are major depressive disorder, pain related to diabetic peripheral neuropathy and stress urinary incontinence
Duloxetine HCl is an acid labile drug which requires an enteric coated system
Mol. Formula- C18H19NOS.HCl
Mol. Wt
m. p ºC

7. Pharmacokinetic Parameters of Duloxetine HCl
t ½ - about 12 hr (8 to 17 hr).
Vd – 1640 l.
> 90 % bound to human plasma proteins.
Bioavailability- 21%
Solubility- 7 mg/ml in water
Dose duloxetine HCl equivalent to duloxetine-20 mg, 30 mg, 40 mg, 60 mg.

8. Plan of Work Preformulation studies
Characterization of drug
Solubility of drug candidate
Stability indicating assay method (by RP-HPLC)
Preparation of suitable delivery system
Choice of Excipients
Formulation optimization
Type of Disintegrants
Ratio of Disintegrants
Percentage of coating

9. Evaluation of the Dosage Form
Particle size (Malvern Metasizer 2000)
Bulk and tapped density
Angle of repose
Hausner’s ratio HR = t/b
Carr's index Ic = (t – b)/t × 100
Friability
Dissolution

10. Materials Duloxetine Hydrochloride (Duloxetine HCl)
Microcrystalline Cellulose (MCC)
Crospovidone (CLPVP)
Sodium Starch Glycolate
Starch
Hydroxy Propyl Methyl Cellulose
Eudragit L-100 (Acrycoat-L100)
Hydrochloric Acid
Tribasic sodium orthophosphate

11. Preparation of pellets

12. Mixing Kneading Extrusion Spheronization Drying Speed – 30 rpm
Spheronization for
10 min
Speed rpm
Drying
For 3 h at 45°C

13. Batch specifications of prepared formulations
Batch Code
Drug
MCC
Disintegrant
Superdisintegrant PM 4%
96% -
CLP1
86%
Crosspovidone
10 %
CLP2
76%
20 %
SG1
Sodium starch Glycolate 10 %
SG2
Sodium starch Glycolate 20 %
SS1
Starch 10 %
SS2
Starch 20 %

14. Microscopic EvaluationPM
CLP1
CLP2

15. SS1
SS2
SG1
SG2

16. Mean Particle Size (µm) Angle of Repose (degree)
Batch Code
Mean Particle Size (µm)
Angle of Repose (degree)
Flow Rate (g/sec)
Hausner’s Ratio PM
766.99
26 °
3.00
0.91
CLP1
830.15
2.50
0.94
CLP2
801.75
14 °
0.87
SG1
863.19
33 °
2.08
0.90
SG2
912.20
1.83
SS1
676.50
18 °
3.63
0.95
SS2
707.75
2.90

17. In vitro dissolution profiles of plain vs. sodium starch glycolate

18. In vitro dissolution profiles of plain vs. CLPVP

19. In vitro dissolution profiles of plain vs. Starch

20. Time
(min)
Plain
Sodium Starch
Glycolate 10%
Glycolate 20%
CLPVP 10%
CLPVP 20%
Starch 10 %
Starch 20% 1
14.61 ± 1.29
7.55 ± 1.20
1.87 ± 0.37
12.09 ± 0.14
13.80 ± 1.01
6.82 ± 0.56
7.14 ± 0.14 5
28.08 ± 2.32
16.60 ± 0.88
12.84 ± 0.78
24.66 ± 0.24
30.92 ± 0.38
19.03 ± 0.62
19.60 ± 0.28 10
38.06 ± 1.74
25.95 ± 0.51
31.41 ± 1.59
33.16 ± 0.51
45.14 ± 0.93
30.58 ± 0.15
30.75 ± 0.37 15
42.50 ± 0.31
32.67 ± 1.10
40.68 ± 1.46
46.33 ± 0.14
55.62 ± 0.38
41.71 ±0.50
42.20 ± 0.24 30
57.67 ± 1.91
48.92 ± 1.36
59.17 ± 0.73
55.60 ± 0.28
67.53 ± 0.89
59.23 ± 0.50
59.73 ± 0.28 45
66.18 ± 2.24
59.90 ± 1.58
71.11 ± 1.23
64.27 ± 0.85
74.24 ± 0.66
71.49 ± 0.25
71.50 ± 0.14 60
71.99 ± 0.67
66.32 ± 0.14
81.48 ± 0.62
70.71 ± 0.43
82.11 ± 0.63
78.95 ± 0.23
78.72 ± 0.38
120
80.66 ± 0.54
75.94 ± 1.25
87.21 ± 0.52
81.57 ± 0.87
83.30 ± 1.45
96.43 ±0.50
96.03 ± 0.15
180
81.51 ±0.18
79.04 ±1.50
96.13 ± 0.64
81.77 ± 0.64
83.99 ± 1.44
101.83±0.25
102.08±0.79
240
82.28 ± 0.84
79.71 ± 2.23
96.41 ± 0.24
82.22 ± 0.88
84.53 ± 1.31
100.93±0.15
101.02±0.79
300
82.64 ± 0.70
79.90 ± 2.15
96.85 ± 0.50
82.34 ± 0.99
84.91 ± 1.48
101.72±0.15
101.89±1.36
360
83.09 ± 0.73
80.34 ± 1.90
97.54 ± 0.36
83.19 ± 1.16
85.04 ± 1.40
102.52±0.14
102.61±0.94

21. Susceptibility of Duloxetine Hydrochloride to acidic conditions
In acidic conditions, it was found to be highly
unstable as 41.35% degradation was observed
in 0.01N HCl at 40°C after 8 h.

22. Duloxetine
Duloxetine
Chromatogram showing the standard solution and degradation behavior of Duloxetine hydrochloride after refluxing in acidic condition 0.01N HCl at 40°C after 8 h

23. Enteric coated capsules filled with duloxetine HCl pellets

24. Enteric Coated Capsules vs. Marketed Preparation
Dissolution profiles of Eudragit L-100 coated capsules (7% coat weight) Vs Dulane 20 (Sun Pharma)

25. Summary
The pellet formulation of Duloxetine HCl was developed using MCC with various disintegrants/superdisintegrants
The batch with MCC showed ± 0.54% drug release after 2h, which was slightly improved by addition of superdisintegrants. The release profiles with superdisintegrants were not as expected. The amount of drug released in case of CLPVP (20%) after 2h was ± 1.45% and in case of sodium starch glycolate (20%) the release was ± 0.52%. But the batch with 20% of starch showed better results as compared with superdisintegrants as well as plain MCC pellets. In this case the amount of drug release after 2h was found to be ± 0.15%.

26. When the drug was exposed to acidic conditions (40°C after 8 h), it was observed that it is highly unstable. The amount of degradation was found to be 41.35% after RP-HPLC analysis.
As the drug is acid labile, enteric coated capsules filled with pellets were developed, which showed comparative dissolution profile with Dulane 20 (Sun Pharma).
The statistical analysis (Mann-Whitney Rank Sum Test) reveled that there was no significant difference in between the two formulations. The f2 value for the formulation was found to be

27. Conclusion
The enteric coated capsule containing pellets of duloxetine HCl was developed, which showed comparative dissolution profile with Dulane 20 (Sun Pharma) which will avoid the direct contact of drug and acidic enteric coating polymer. This pellet formulation of the drug will offer distinct pharmaceutical technological advantage over tablet dosage form.

28. Thank You