Formulation, Characterization of Formulation, Characterization of Pellets of Duloxetine Hydrochloride Pellets of Duloxetine Hydrochloride

by Extrusion and Spheronizationby Extrusion and Spheronization

Prof. V. R. SinhaUniversity Institute of Pharmaceutical Sciences, Center for

Advanced Studies, Panjab University, ChandigarhINDIA

ObjectiveObjective

The objective of the present The objective of the present

investigation was to prepare and investigation was to prepare and

characterize pellets of Duloxetine characterize pellets of Duloxetine

hydrochloride by using the technique hydrochloride by using the technique

of extrusion- spheronization.of extrusion- spheronization.

PelletizationPelletization

Agglomeration process that converts fine Agglomeration process that converts fine

powders of bulk drugs & excipients into powders of bulk drugs & excipients into

small, free-flowing units referred to as small, free-flowing units referred to as

pellets.pellets.

Rationale for pelletizationRationale for pelletization

FlexibilityFlexibility in dosage form design & development in dosage form design & development

Improve the Improve the safety & efficacysafety & efficacy of bioactive agents of bioactive agents

Disperse freelyDisperse freely in the g.i.t. in the g.i.t.

Reduce variationReduce variation in in gastric emptyinggastric emptying rates rates

ReduceReduce the inter- & the inter- & intra-subject variabilityintra-subject variability

Avoid High local concentrationsAvoid High local concentrations

Contd…

Controlled release pellets an be manufacturedPellets have a low surface area-to-volume ratio &

provide an ideal shape for the application of film

coatingReproducible & uniform fill weights in capsulesPellets can be made aesthetically appealingAverage transit time of pellets in the intestine can be

increased Pellets are less susceptible to dose dumping

DuloxetineDuloxetine HydrochlorideHydrochloride

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

O

NH .HCl

S

Mol. Formula- C18H19NOS.HCl

Mol. Wt.- 333.88

m. p.- 163-167 ºC

Pharmacokinetic Parameters of Pharmacokinetic Parameters of Duloxetine HClDuloxetine HCl

t t ½ ½ - about - about 12 hr12 hr (8 to 17 hr). (8 to 17 hr).

VVd d – – 1640 l1640 l..

> > 90 %90 % bound to human plasma proteins. bound to human plasma proteins. Bioavailability- Bioavailability- 21%21% Solubility- Solubility- 7 mg/ml7 mg/ml in water in water Dose duloxetine HCl equivalent to Dose duloxetine HCl equivalent to duloxetine-20 mg, duloxetine-20 mg,

30 mg, 40 mg, 60 mg.30 mg, 40 mg, 60 mg.

Plan of WorkPlan of Work Preformulation studiesPreformulation studies

Characterization of drugCharacterization of drug Solubility of drug candidateSolubility of drug candidate Stability indicating assay method (by RP-HPLC) Stability indicating assay method (by RP-HPLC)

Preparation of suitable delivery systemPreparation of suitable delivery system Choice of ExcipientsChoice of Excipients Formulation optimizationFormulation optimization

Type of DisintegrantsType of Disintegrants Ratio of DisintegrantsRatio of Disintegrants Percentage of coatingPercentage of coating

Evaluation of the Dosage FormEvaluation of the Dosage Form

Particle size (Malvern Metasizer 2000)Particle size (Malvern Metasizer 2000)Bulk and tapped density Bulk and tapped density Angle of repose Angle of repose Hausner’s ratio Hausner’s ratio HR = HR = t/t/bb Carr's index Carr's index Ic = (Ic = (t – t – b)/b)/t t × 100× 100FriabilityFriabilityDissolutionDissolution

MaterialsMaterials

Duloxetine Hydrochloride (Duloxetine HCl)Duloxetine Hydrochloride (Duloxetine HCl) Microcrystalline Cellulose (MCC)Microcrystalline Cellulose (MCC) Crospovidone (CLPVP)Crospovidone (CLPVP) Sodium Starch GlycolateSodium Starch Glycolate Starch Starch Hydroxy Propyl Methyl CelluloseHydroxy Propyl Methyl Cellulose Eudragit L-100 (Acrycoat-L100) Eudragit L-100 (Acrycoat-L100) Hydrochloric AcidHydrochloric Acid Tribasic sodium orthophosphateTribasic sodium orthophosphate

Preparation of pelletsPreparation of pellets

Mixing

Extrusion

Drying

Spheronization

Kneading

Spheronization for 10 minSpeed - 2100 rpm

Speed – 30 rpm

For 3 h at 45°C

Batch specifications of prepared Batch specifications of prepared formulationsformulations

Batch Batch CodeCode

DrugDrug MCCMCC DisintegrantDisintegrant SuperdisintegrantSuperdisintegrant

PMPM 4%4% 96%96% -- --

CLP1CLP1 4%4% 86%86% -- CrosspovidoneCrosspovidone

10 %10 %

CLP2CLP2 4%4% 76%76% -- CrosspovidoneCrosspovidone

20 %20 %

SG1SG1 4%4% 86%86% -- Sodium starch Sodium starch Glycolate 10 %Glycolate 10 %

SG2SG2 4%4% 76%76% -- Sodium starch Sodium starch Glycolate 20 %Glycolate 20 %

SS1SS1 4%4% 86%86% Starch 10 %Starch 10 % --

SS2SS2 4%4% 76%76% Starch 20 %Starch 20 % --

Microscopic EvaluationMicroscopic Evaluation

CLP1PM

CLP2

SS1 SS2

SG1 SG2

Batch Batch CodeCode

Mean Mean Particle Particle

Size (Size (µm)µm)

Angle of Angle of Repose Repose (degree)(degree)

Flow Rate Flow Rate (g/sec)(g/sec)

Hausner’s Hausner’s RatioRatio

PMPM 766.99766.99 26 26 °° 3.003.00 0.910.91

CLP1CLP1 830.15830.15 26 26 °° 2.502.50 0.940.94

CLP2CLP2 801.75801.75 14 14 °° 2.502.50 0.870.87

SG1SG1 863.19863.19 33 33 °° 2.082.08 0.900.90

SG2SG2 912.20912.20 33 33 °° 1.831.83 0.940.94

SS1SS1 676.50676.50 18 18 °° 3.633.63 0.950.95

SS2SS2 707.75707.75 18 18 °° 2.902.90 0.940.94

0

20

40

60

80

100

120

0 100 200 300 400

Time (min)

% D

rug

Rel

ease

± S

.D.

Plain

Sodium Starch Glycolate 10%

Sodium Starch Glycolate 20%

In vitro dissolution profiles of plain vs. sodium starch glycolate

0

10

20

30

40

50

60

70

80

90

100

0 50 100 150 200 250 300 350 400

Time (min)

% D

rug

Re

lea

se

± S

.D.

Plain

CLPVP 10%

CLPVP 20%

In vitro dissolution profiles of plain vs. CLPVP

0

20

40

60

80

100

120

0 100 200 300 400

Time (min)

% D

rug

Rel

ease

d ±

S.D

.

Plain

Starch 10 %

Starch 20%

In vitro dissolution profiles of plain vs. Starch

Time (min)

PlainSodium StarchGlycolate 10%

Sodium StarchGlycolate 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

Susceptibility of Duloxetine Hydrochloride to Susceptibility of Duloxetine Hydrochloride to

acidic conditionsacidic conditions

In In acidic conditionsacidic conditions, it was found to be highly, it was found to be highly

unstable as 41.35% degradation was observedunstable as 41.35% degradation was observed

in 0.01N HCl at 40°C after 8 h. in 0.01N HCl at 40°C after 8 h.

Chromatogram showing the standard solution and degradation behavior of Duloxetine hydrochloride after refluxing in acidic condition 0.01N HCl at 40°C after 8 h0.01N HCl at 40°C after 8 h

Duloxetine Duloxetine

Enteric coated capsules filled with duloxetine HCl pellets

0

20

40

60

80

100

120

0 200 400 600 800 1000 1200 1400 1600

Time (min)

% D

rug

Rel

ease

d ±

S.D

.

Enteric Coated Capsules

Marketed Preparation

Enteric Coated Capsules vs. Marketed Preparation

Dissolution profiles of Eudragit L-100 coated capsules (7% coat weight) Vs Dulane 20 (Sun Pharma)

SummarySummary

The pellet formulation of Duloxetine HCl was developed using MCC The pellet formulation of Duloxetine HCl was developed using MCC

with various disintegrants/superdisintegrantswith various disintegrants/superdisintegrants

The batch with MCC showed The batch with MCC showed 80.66 ± 0.54% drug release after 2h,

which was slightly improved by addition of superdisintegrants. The superdisintegrants. The

release profiles with superdisintegrants were not as expected. The release profiles with superdisintegrants were not as expected. The

amount of drug released in case of CLPVP (20%) after 2h was 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 But the batch with 20% of starch showed better results

as compared with superdisintegrants as well as plain MCC pellets. In as compared with superdisintegrants as well as plain MCC pellets. In

this case the amount of drug release after 2h was found to be this case the amount of drug release after 2h was found to be 96.03 ± 96.03 ±

0.15%.0.15%.

When the drug was exposed to When the drug was exposed to acidic conditionsacidic conditions (40°C after 8 (40°C after 8

h), it was observed that it is h), it was observed that it is highly unstablehighly unstable. The amount of . The amount of

degradation was found to be degradation was found to be 41.35%41.35% after RP-HPLC analysis. after RP-HPLC analysis.

As the drug is acid labile, As the drug is acid labile, enteric coated capsulesenteric coated capsules filled with filled with

pellets were developed, which showed comparative dissolution pellets were developed, which showed comparative dissolution

profile with Dulane 20 (Sun Pharma). profile with Dulane 20 (Sun Pharma).

The statistical analysis (Mann-Whitney Rank Sum Test) reveled The statistical analysis (Mann-Whitney Rank Sum Test) reveled

that there was that there was no significant difference in between the two no significant difference in between the two

formulationsformulations. The f2 value for the formulation was found to be . The f2 value for the formulation was found to be

58.92. 58.92.

ConclusionConclusion

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