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-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.- 333.88 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 Spheronization Drying Speed – 30 rpm Spheronization for 10 min Speed - 2100 rpm Drying For 3 h at 45°C

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 %

Microscopic Evaluation PM CLP1 CLP2

SS1 SS2 SG1 SG2

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

In vitro dissolution profiles of plain vs. sodium starch glycolate

In vitro dissolution profiles of plain vs. CLPVP

In vitro dissolution profiles of plain vs. Starch

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

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 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.

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