Continuous twin-screw melt granulation of thermally labile drug case - PowerPoint PPT Presentation

Continuous twin-screw melt granulation of thermally labile drug – case study TONY LISTRO, MS MBA FOSTER DELIVERY SCIENCE 9 TH AMERICAN DRUG DELIVERY & FORMULATION SUMMIT BOSTON, SEPTEMBER 9, 2019 1

Objectives Twin-screw melt granulation offers many advantages over roller compaction.  To investigate the effect of formulation and process variables on the physicochemical properties of granules • Binder type and binder particle size • Screw design, barrel temperature, screw speed and feed rate  To understand the mechanisms and physicochemical changes during granulation • Dead-stop test 2

Presentation outline 1. Introduction of melt granulation and gabapentin (GABA), a thermally labile drug with poor compaction property. 2. Selection of thermal binder and effect of thermal binder on the properties of GABA granules 3. Effect of processing conditions on the properties of GABA granules 4. Future studies and conclusions 3

Twin-Screw Melt Granulation • Continuous manufacturing • On-line and real time monitoring of product quality • Short granulation time and wider processing window Granulation by TSE • Reduction in binder (solution) level • Uniform distribution of formulation components • Less undesired physicochemical changes • Use low-melting or thermoplastic materials as binders Wet Melt • Energetic materials/explosives; powder granulation granulation metallurgy • Improved flow and flow properties than roller-compacted granules 4

Nucleation mechanism of melt granulation: Depend on particle size and viscosity of binder Distribution • Binder with low melt-viscosity • Molten binder is distributed onto the surfaces of solid particles • Nuclei are formed by collision between the wetted particle Immersion • Thermoplastic binder with high melt viscosity • Adhesion of solid particles onto the surface of molten binder particles James S, et al. Handbook of Pharmaceuitcal Granulation Technology. Taylor & Francis group LLC. 2005. 390-392. 5

Gabapentin (GABA) as a “Model drug” Goal of the study • Identify formulation and process to (1) Improve compactability of gabapentin and (2) minimize processing-induced chemical degradation of gabapentin Gabapentin as a “model drug” for melt granulation • High-dose, poorly compressible drug • Poor thermal stability • Current commercial process: high-shear or fluidized-wet granulation. High impurity content of GABA tablets has been an real issue. • During wet granulation, GABA is solubilized. The presence of polymeric binders prevent GABA from recrystallize during drying. The solubilized GABA undergoes significant degradation during the storage. 6

Properties of Gabapentin Properties Anti epileptic Indication White to off - white, crystalline solid Description Form II, the most stable form, is used in this study 171 . 24 g / mol MW 162 - 166°C Melting point 3 . 7 ( carboxylate ) , 10 . 7 ( amine ) pKa BCS class III ( high solubility and low permeability ) BCS class Solubility pH-dependent solubility; soluble in water (100 mg/mL) Particle size 6.1 μ m (d10), 55.24 μ m (d50), 215.64 μ m (d90) Others Crystalize rapidly, amorphous GABA could not be prepared USP39 NF34 Gabapentin 7 https://pubchem.ncbi.nlm.nih.gov/compound/gabapentin#section=Top

Degradation pathway in solution & solid state: lactamization (GABA-L) • Gabapentin degrades to a cyclic lactam via an intramolecular cyclization reaction triggered by a nucleophilic attack of the COOH group by the N of the amino group, followed by a dehydration reaction • The degradation reaction is irreversible • USP specification of Gaba-lactam: NMT 0.4% Zhizin Z, et al. The stabilizing effect of moisture on the solid-state degradation of gabapentin. AAPS PharmSciTech. 2011. 12(3):924-931. 8

GABA undergoes lactamization upon melting 0 100 80 Dehydration due -10 Heat flow (W/g) to degradation ( ~ 10.5%w/w) % weight 60 -20 40 Overlap between melting -30 and degradation 20 Tm ~ 174 ° C 0 -40 50 100 150 200 250 300 350 400 Temperature (°C) 9

Melting and lactamization of GABA under hot-stage PLM 25 ° C 174 ° C 176 ° C (with bubble) 180 ° C 183 ° C 184 ° C 10

Preliminary study: binder selection Miscibility between GABA and binders The experiment from DSC and Hot stage PLM confirm that Gabapentin is immiscible with binders Hydrophobic binder Hydrophilic binder Thermoplastic polymer Glycerol behenate (Compritol) HPC ELF (Klucel) PEG 8000 wt% hydroxypropyl groups: 53-81 Kittikunakorn N , Sun CC, Zhang F*. Effect of screw profile and processing conditions on physical transformation and chemical degradation of gabapentin 11 during twin-screw melt granulation. Eur J Pharm Sci . 131:243-253 ( 2019 ).

Too good miscibility of GABA and binders is not desired! Hold at 80 ° C Hold at 100 ° C Hold at 140 ° C PEG (Tm ~ 60 ° C) Compritol (Tm ~ 70 ° C) HPC (Tg ~ 0 ° C, soften at 100-140 ° C) 12

80% GAGB and 20% binder; Feed rate 10 g/min, Screw speed 100 rpm GB-PEG8000 GB-Compritol 888 ATO GB-HPC ELF Zone 1 Zone 2 Zone 3 Binders 80 ° C 80 ° C 40 ° C GB-PEG8000 90 ° C 90 ° C 60 ° C GB-Compritol GB-HPC ELF 120 ° C 120 ° C 70 ° C Leistritz nano 16 Open-end discharge 13

SEM Images of Granules GABA+PEG/1000 X GABA+Compritol/1000 X GAGB+HPC/1000 X 14

Melt granulation significantly improves compaction properties. HPC is the most effective. 5.0 5.0 5.0 Melt granulation Melt granulation (20%Compritol+GB) (20%PEG 8000+GB) 4.0 4.0 4.0 Tensile strength (MPa) Tensile strength (MPa) Direct compression Tensile strength (MPa) Direct compression (20%Compritol+GB) (20%PEG8000+GB) 3.0 3.0 3.0 Melt granulation (20%HPC ELF+GB) Direct compression 2.0 2.0 2.0 (20%HPC ELF+GB) 1.0 1.0 1.0 0.0 0.0 0.0 0.0 50.0 100.0 150.0 0.0 50.0 100.0 150.0 0.0 50.0 100.0 150.0 Compression pressure (MPa) Compression pressure (MPa) Compression pressure (MPa) • Mill the granule and collect the granule between 20-60 mesh (250-850 μ m)  mix with 1% Mg stearate  compress into tablet 15

Degradation of GABA granules upon storage USP specification for GABA-L: NMT 0.4% Induction-sealed HDPE bottles, desiccated 16

Degradation of gabapentin USP specification for GABA-L: NMT 0.4% 0.060 • Higher barrel temperature led to 20%HPC ELF+GB higher level of degradant 20%PEG8000+GB 0.050 • At the same temperature : HPC ELF- 20%Compritol+GB based granule shown higher % 0.040 GABA-lactam than Compritol and %Impurity PEG 8000-based granules 0.030 0.020 0.010 0.000 85 90 95 100 105 110 Barrel temperature (°C) 17

Particle size reduction during melt granulation GABA in HPC ELF based formulation has the smallest particle x(10 %) x(50 %) x(90 %) Param. 3 Opt. concentration size  high mechanical stress resulted in breakage of drug µm µm µm % 21.72 63.12 116.13 33.47 crystals and amorphization  highest impurity 7.57 42.88 96.49 25.69 4.69 21.41 49.06 26.51 1.57 10.45 41.90 30.75 1.7 1.6 1.5 Gabapentin drug substance Density distribution q3* 1.4 1.3 1.2 1.1 Chloroform Compritol-GABA granules 1.0 0.9 0.8 0.7 PEG8000-GABA granules 0.6 0.5 Acetone 0.4 0.3 HPC-GABA granules 0.2 0.1 0.0 0.4 0.6 0.8 1.0 2 4 6 8 10 20 40 60 80 100 particle size / µm 18

Development of granule structure during the granulation along screw profile 20% HPC EXF + Gabapentin 120 ° C 120 ° C 70 ° C 19

Particle size of gabapentin along screw profile (EXF2-4) 4) • Sample the granules from each zone • Disperse in acetone in order to dissolve HPC Feeding zone • Measure the particle size of gabapentin Zone 1 Particle size of gabapentin decrease Zone 2 Zone 3 Zone 2 Feeding zone Zone 1 120 ° C 120 ° C 70 ° C Zone 3 Granules 20

Binder Distribution on the surface of granules: Time-of-Flight Secondary Ion Mass Spectrometry Z1 PM (TOF-SIMS) CH 2 N - C 2 H 3 O - Total PM Z1 Z2 Z3 Z2 Z3 21

Melt rheology of binders • Melt viscosity of HPC ELF (pseudoplastic) >> melt viscosity of PEG 8000 and Compritol (Newtonian fluid). • The high viscosity of HPC melt during granulation resulted in high shear stress that led to significant particle size reduction. 22

When granules were stored in open containers, slower degradation at higher humidity – due to crystallization of amorphous GABA GB-HPC ELF Granules GABA drug substance 0.30 0.02 40°C, 10%RH 40°C, 30%RH 0.25 0.02 40°C, 75%RH %GABA-L %GABA-L 40C, 10%RH 0.20 0.01 40C, 30%RH 40C, 75%RH 0.01 0.15 0.00 0.10 1 2 3 4 0 1 2 3 4 WEEK WEEK “The stabilizing effect of moisture on the solid - state degradation of gabapentin”, Z. Zong, AAPS PharmSciTech, 12(3) 925-31 (2011) 23

Studying HPC of different particle size • HPC ELF : D50 ~ 160 μ m • HPC EXF : D50 ~ 50 μ m 80% Gabapentin + 20% Binders • Spray-dried HPC : D50 ~ 10 μ m 80% GAGB and 20% binder Feed rate 10 g/min, Screw speed 100 rpm 24

Effect of HPC particle size on GABA granule size 35.00 30.00 25.00 >1180 20.00 850-1180 %w/w 600-850 15.00 425-600 250-425 10.00 150-250 <150 5.00 0.00 HPC ELF HPC EXF HPC SD Granules size ( μ m) 25