for for Dissolution Testing Dissolution Testing Some Practical Considerations Some Practical Considerations Vilayat A. Sayeed, Ph.D. Director, Division of Chemistry III Office of Generic Drugs OPS/CDER/FDA April 28-30, 2008 Crystal City, Arlington, VA 2 Objectives To understand the influence of formulation and processing variables on the dissolution and disintegration time of IR tablets To determine the relationship, if any, between dissolution and disintegration time for IR tablets of a highly soluble drug 3 Disintegration vs. Dissolution De-aggregation Dissolution Tablet Granules or Aggregates Particles Drug in Solution (in-vitro/in-vivo) Disintegration 4 ICH Q6A Decision Tree 7(1) Disintegration acceptance criteria with an upper time limit are acceptable if the following conditions are satisfied: Dosage form is not designed to produce modified release Dose/ solubility < 250 mL through out the physiological pH range (pH 1.2 - 6.8) at 37C Dissolution > 80% in 15 min at pH 1.2, 4.0, and 6.8 A relationship has been determined between disintegration and dissolution 5 Drug Selection Verapamil HCl used as model drug Product Classification Dose / Solubility < 250 mL at pH range 1.2 - 6.8 Solubility at different pH (Analytical Profiles) Solvent Water/pH solubility (mg/mL) pH 2.32 82 pH 3.05 78 pH 4.65 89 pH 4.86 82 pH 5.59 76 pH 6.35 83 pH 6.54 46 pH 6.76 11 pH 7.32 0.44 6 Experiment Design Verapamil HCl used as model drug Product Classification Dose / Solubility < 250 mL at pH range 1.2 - 6.8 Formulation ingredients Drug 10.0% Filler 75.0% Binder 4.0% Disintegrating agent (or absent) 10.0% (0%) Magnesium stearate 0.5% Talc 0.5% 2x2x3x2 (24 batches) full-factorial design used 7 Variables and Batch Codes Different batches of IR tablets prepared by varying Filler DCP / LMH Binder PVP / HPMC Disintegrating Agent NaCMC / MCC / None Tablet hardness 6 Kgf / 10 Kgf Each batch assigned a five digit alpha-numeric code V* 1 * 2 * 3 * 4 , where * 1 = D for DCP L for LMH * 2 = P for PVP H for HPMC * 3 = A for NaCMC M for MCC X for None * 4 = 1 for 6 Kgf 2 for 10 Kgf (tablet hardness) 8 Manufacturing Process Drug + filler blended for 5 min in a planetary mixer Granulation performed in a fluidized- bed granulator Aqueous binder solution sprayed at constant rate Dried granules blended with the disintegrating agent (if present), talc and magnesium stearate for 5 minutes in a V-blender Granules compressed on a tablet press to obtain tablets with 6 and 10 Kgf hardness 9 Test Procedures USP30 <701> Disintegration procedure for uncoated tablets. n = 6 USP30 Dissolution test procedure for Verapamil HCl tablets. n = 6 USP method II (Paddle method) at 50 rpm Media: 900 mL 0.01 N HCl UV analysis at 278 nm at 15 and 30 minutes USP limit: Q NLT 75% in 30 min Dissolution test also performed in pH 4.0 and pH 6.8 phosphatebuffers for selected batches 10 Results Disintegration Time ranged from <1 to >60 min Dissolution @ 30 min ranged from 18.1 to 100.5% Q < 75% for 14 batches (failed as per USP criteria) Variable analysis of the 14 failed batches: DCP: LMH 12:2 NaCMC: MCC: None 4:4:6 PVP: HPMC 6:8 6 Kgf: 10 Kgf (Hardness) 7:7 Dissolution @ 15 min at pH 4.0, 6.8 & 0.1N HCL Q > 80% for VLHA1 and VLHA2 Q < 80% for at least one tablets at all pHs for VLPA1, VLPA2, VLPX1 and VLPM1 11 Variation in Disintegration Time 0 10 20 30 40 50 60 A1 A2 M1 M2 X1 X2 Disintegrating Agent and Tablet Hardness D i s i n t e g r a t i o n
T i m e
( m i n ) DH LH DP LP Filler - Binder Dark color: DCP; Light color: LMH; (Horizontal): HPMC; [|] (Vertical) : PVP 12 Dissolution (at 30 min) 0 20 40 60 80 100 120 A1 A2 M1 M2 X1 X2 Disintegrating Agent and Tablet Hardness D i s s o l u t i o n
a t
3 0
m i n u t e s
( %
w / w ) DH LH DP LP Filler - Binder USP limit Dark color: DCP; Light color: LMH; (Horizontal): HPMC; [|] (Vertical): PVP 13 Dissolution vs. Disintegration 0 20 40 60 80 100 0 4 8 12 16 20 Disintegration Time (minutes) D i s s o l u t i o n
( % w / w ) 30 min 15 min > USP limit ICH Q6A Dicision Tree 7(1) 14 Q 80% @ 15 minutes 70 75 80 85 90 95 100 105 0 1 2 3 4 5 6 Disintegration Time (minutes) D i s s o l u t i o n
( % w / w ) VLHA1 VLHA2 VLPA1 VLPA2 VLPM1 VLPX1 15 Effect of Filler 0 20 40 60 80 100 0 4 8 12 16 20 Disintegration Time (min) D i s s o l u t i o n
( % w / w ) DCP 15 min LMH 15 min DCP 30 min LMH 30 min > 16 Effect of Disintegrating Agent 0 20 40 60 80 100 0 4 8 12 16 20 Disintegration Time (min) D i s s o l u t i o n
( % w / w ) A-15 M-15 X-15 A-30 M-30 X-30 > 17 Effect of Binder 0 20 40 60 80 100 0 4 8 12 16 20 Disintegration Time (minutes) D i s s o l u t i o n
( % w / w ) H-15 P-15 H-30 P-30 > 18 Variable Effect Analysis Dissolution (at 15 and 30 min) influenced by Filler L > D p < 0.0001 Disintegrating agent A > M > X p = 0.002 Binder P > H p = 0.02 Disintegration time influence by Disintegrating agent A > M > X p < 0.0001 Filler L > D p = 0.0002 Binder P > H p = 0.004 Hardness 1 > 2 p = 0.02 Filler * Disintegrating Agent p = 0.0004 Filler * Binder p = 0.008 Binder * Disintegrating Agent p = 0.03 19 Conclusions Dissolution influenced by formulation variables Disintegration time influenced by all four variables Filler and disintegrating agent showed most significant influences on both test parameters No relationship observed between dissolution and disintegration time Only two test batches (out of 24) met the criteria for using disintegration test for drug release 20 Acknowledgement Abhay Gupta, Robert Hunt, Mansoor A. Khan, Gary Buehler, Helen Winkle