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
 Objective

The objective of the present investigation

was to prepare and characterize pellets of
Duloxetine hydrochloride by using the
technique of extrusion- spheronization.
 Pelletization

Agglomeration process that converts fine

powders of bulk drugs & excipients into
small, free-flowing units referred to as
pellets.
 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…
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
 Duloxetine Hydrochloride

Categorized as an antidepressants as
dual inhibitor of serotonin and nor- N
H .HCl
epinephrine reuptake S

O
The clinical indications of the drug are
major depressive disorder, pain related to
diabetic peripheral neuropathy and stress
urinary incontinence
Mol. Formula- C18H19NOS.HCl
Duloxetine HCl is an acid labile drug Mol. Wt.- 333.88
which requires an enteric coated system m. p.- 163-167 ºC
 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.
 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
 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
 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
Preparation of pellets
 Mixing

Kneading

Extrusion Speed – 30 rpm

Spheronization for
Speed - 2100 rpm Spheronization
10 min

Drying For 3 h at 45°C

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

PM CLP1

CLP2
SS1 SS2

SG1 SG2
Batch Mean Angle of Flow Rate Hausner’s
Code Particle Repose (g/sec) Ratio
Size (µm) (degree)
PM 766.99 26 ° 3.00 0.91
CLP1 830.15 26 ° 2.50 0.94
CLP2 801.75 14 ° 2.50 0.87
SG1 863.19 33 ° 2.08 0.90

SG2 912.20 33 ° 1.83 0.94

SS1 676.50 18 ° 3.63 0.95

SS2 707.75 18 ° 2.90 0.94
 120

100
% Drug Release ± S.D.

80

Plain
60

Sodium Starch Glycolate 10%

40
Sodium Starch Glycolate 20%
20

0
0 100 200 300 400

Time (min)

In vitro dissolution profiles of plain vs. sodium starch

glycolate
 100

90

80
% Drug Release ± S.D.

70

60
Plain
50
CLPVP 10%
40
CLPVP 20%
30

20

10

0
0 50 100 150 200 250 300 350 400

Time (min)

In vitro dissolution profiles of plain vs. CLPVP

 120
% Drug Released ± S.D.

100

80
Plain
60 Starch 10 %
Starch 20%
40

20

0
0 100 200 300 400
Time (min)

In vitro dissolution profiles of plain vs. Starch

Time Sodium Starch Sodium Starch
Plain CLPVP 10% CLPVP 20% Starch 10 % Starch 20%
(min) Glycolate 10% Glycolate 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
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.
 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
Enteric coated capsules filled with
duloxetine HCl pellets
Enteric Coated Capsules vs. Marketed Preparation
120

100
% Drug Released ± S.D.

80

Enteric Coated Capsules

60
Marketed Preparation

40

20

0
0 200 400 600 800 1000 1200 1400 1600
Time (min)

Dissolution profiles of Eudragit L-100 coated capsules

(7% coat weight) Vs Dulane 20 (Sun Pharma)
 Summary
 The pellet formulation of Duloxetine HCl was developed using MCC
with various disintegrants/superdisintegrants

 The batch with MCC showed 80.66 ± 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 83.30 ±
1.45% and in case of sodium starch glycolate (20%) the release was
87.21 ± 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 96.03 ±
0.15%.
 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
58.92.
 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.