The Role of Polymer Excipients in Hot Melt Extrusion A Continuous Manufacturing Process Nigel Langley ExcipientFest May 1, 2018 Hot-Melt Extrusion A Continuous Manufacturing Process Principle of HME 2 1
Hot-Melt Extrusion Technology A poorly soluble crystalline API and an amorphous polymer are transferred into a solid dispersion with thermal and mechanical energy Solid dispersion API in polymer poorly soluble crystalline API E Hot Melt Extrusion Amorphous polymer solvent Extruder Hot Melt Extrusion is one key technology for the preparation of solid dispersions 2
Biopharmaceutical Classification System BCS High Solubility Low Solubility High Permeability Class I Class II Low Permeability Class III Class IV Source: G.L. Amidon, H. Lennermäs, V.P. Shah, J.R. Crison, Pharm. Res. 12 (1995), 413-420 The BCS classifies APIs by their solubility and permeability for cell membranes. There is a trend for recent API candidates to fall in the low solubility class II (or IV). Solid Solutions and Solid Dispersions Relevant Types of Solid Dispersions Drug: dissolved crystalline amorphous molecularly Polymer: amorphous amorphous amorphous Thermodynamic almost stable unstable stable (drug below stability solubility) (kinetically controlled) saturation 3
Parameters to Consider Relevant Polymer Characteristics Long term stability Targeted release profile Glass transition temperature Hygroscopicity Drug + Polymer Melt viscosity Physicochemical properties of active Thermostability of drug & polymer Solution & solubilizing capability 7 Polymer Properties Basic Requirements for Polymers Thermoplastic behavior Suitable Tg High thermal stability Low hygroscopicity No toxicity High or no solubilization capability deformability is essential 50 180 C 50 180 C prevents crystallization application of large amounts thermodynamically stable formulation 4
Polymers for Hot Melt Extrusion Polymers for Different Release Profiles IR Enteric SR Kollidon VA 64 Kollidon K17, K30, K90 Kollicoat IR Soluplus Kolliphor P 188 / 407 HPMC HPC Eudragit E PEG Polyvinyl alcohol Kollicoat MAE 100-55 Kollicoat MAE 100 P Eudragit L 100-55 HPMCAP HPMCAS Kollidon SR Polyvinyl acetate Ethyl cellulose Eudragit RS 9 Matrix polymers for solid dispersions Kollidon 12 PF, 17 PF (Povidone) N Hydrophilicity / Polarity Kollidon VA 64 (Copovidone) n N n m Kollidon SR (PVAc) (modified release) n Lipophilicity / Hydrophobicity Kollicoat IR, Kollicoat Protect Soluplus N H o o Kollicoat MAE 100P (enteric release) n m H 5
Solvent Screening Procedure Film Test for Solid Solution Capacity Active in solvent Polymer in solvent 1:1 dried polymer film Preparation of films with 10% to 50 % drug content bservation of film stability drug must not recrystallize Goal: stable solid solution with 50% drug load API Drug load model drugs Solid Solution Capacity Polymer Drug content [% dissolved in polymer] Fenofibrate Carbamazepine Itraconazole Kollidon VA 64 25 33 33-50 >50> Soluplus 33-50 33-50 >50> Kollidon 12 PF 25 33 25 33 33-50 Kollidon 17 PF <25< 25 33 33-50 Kollidon 30 <25< < <25 >50> Kollidon 90 F <25< < <25 >50> Kollidon SR 25 33 33-50 >50> Kollicoat MAE 100P <25< > >50 n.d. Kollicoat IR <25< < <25 n.d. Kollicoat Protect <25< < <25 n.d. Lutrol F 127 <25< < <25 <25< with 10 % PEG 1500 with 20 % PEG 1500 6
Glass Transition Temperatures of matrix polymers Temperature [ C] 200 180 160 140 120 100 80 60 40 20 0 70 Soluplus 101 90 Kollidon 12PF 149 156 Kollidon 90F 152 39 114 118 Kollicoat MAE 130 HPC 186 Usually, extrusion requires temperatures of min. 20-30 C > Tg Polymers for HME Solid Dispersions / Solid Solutions Matrix Formers Plasticizers Solubilizers N n m Kollidon VA 64 Established matrix former especially in hot melt extrusion Soluplus Kollidon VA 64 Kollidon VA 64 Fine Kollidon 12 PF Kollidon 17 PF Kollidon 25 / 30 Kollidon 90 Kollidon SR Kollicoat IR Kollicoat Protect Kollicoat MAE 100P Kolliphor P 188 Kolliphor P 188 micro Kolliphor P 407 Kolliphor P 407 micro Kollisolv GTA Kolliwax GMS I Kolliwax SA Kollisolv PEG E 300 Kollisolv PEG E 400 Kollisolv PEG 1450 Kolliphor HS 15 Kolliphor RH 40 Kolliphor EL/ ELP Kolliphor PS 20 Kolliphor PS 60 Kolliphor PS 80 Kolliphor SLS / Fine Kolliphor P 188 Kolliphor P 407 Soluplus Soluplus Innovative matrix and solubilizer in one taylored for HME use increases solubility and bioavailability 7
Melt Viscosities Melt Viscosity as a Function of Temperature Viscosity [Pas] 1000000 100000 10000 1000 100 Kollidon VA 64 Soluplus Kollidon 12 PF Kollidon 17 PF Kollidon 30 Kollidon 90 F Kollidon SR Kollicoat MAE 100P Kollicoat IR Kollicoat Protect ptimal melt viscosity range for HME 10 120 140 160 180 200 220 240 Temperature [ C] Shear stress controlled rotational rheometer (Rheometrics SR5), plate to plate geometry, angular frequency: 16 rad/s Influence of Plasticizers on Extrusion Temperatures Temperature [ C] Kollidon 12 PF Kollidon VA 64 Pure Polymer + 10 % Kolliphor P 188 Soluplus Kollidon 17 PF Kollidon SR Kollicoat IR The addition of 10% plasticizer significantly decreases processing temperatures 8
Appearance of polymer extrudates at specific extrusion temperatures Kollidon VA 64 (160 C) Kollidon 12 PF (100 C) Kollicoat IR (160 C) Kollidon SR (180 C) Soluplus (145 C) Kollidon 17 PF (175 C) Kollicoat Protect (160 C) Kolliphor P407 (60 C) Kollidon VA 64 extrudates prepared at different temperatures 160 C 180 C 220 C 240 C w(log(m)) 0,90 0,80 0,70 0,60 0,50 0,40 0,30 0,20 0,10 Kollidon VA 64 LT 76964875L0 extruded 160 C Kollidon VA 64 LT 76964875L0 0,00 1.000 10.000 100.000 1.000.000 10.000.000 M/Da Kollidon VA 64 can be extruded up to 220 C without degradation 9
Soluplus - The Solid Solution PEG 6000/ vinylcaprolactam/ vinyl acetate grafted copolymer 13/57/30 Tg: ~ 70 C soluble in water, acetone, ethanol Soluplus combines the benefits of a solid solution and an excellent solubilizer Soluplus Saturation solubility in phosphate buffer ph 7.0 [g/100 ml] 0.35 0.30 0.25 Soluplus Pure API 0.20 0.15 0.10 0.05 0.00 ~0.001 ~0.001 ~0.001 ~0.001 ~0.0001 ~0.0001 ~0.0001 10% solubilizer solution, saturation solubility detected after 72h stirring Soluplus strongly increases the solubility for APIs with different chemical structures 10
Soluplus Saturation solubility in phosphate buffer ph 7.0 [g/100 ml] 0.35 0.30 0.25 Soluplus Kolliphor RH40 Kolliphor PS 80 Kolliphor HS15 Kolliphor P 407 0.20 0.15 0.10 0.05 0.00 10% solubilizer solution, saturation solubility detected after 72h stirring With 4 out of 10 APIs Soluplus shows the highest solubilization capacity! Soluplus Thermal Stability Thermostability Extrusion parameters 120 260 C 1kg/h At extrusion temperatures up to 160 C nearly colourless extrudates 11
Analytical Results Polymer Stability During Extrusion - Soluplus Test parameter Identification (IR) ph-value Ester value [mg KH/g] Vinyl acetate [ppm] Vinyl caprolactame [ppm] Caprolactame [g/100g] Ethylenglykole [ppm] Acetic acid / Acetate [ppm] Peroxide [ppm] Molecular weight Mw [g/mol] Powder conf. 4.1 197 <2 <10 0.3 <100 365 <20 118,000 Extrudate Extrudate [extruded at 140 C] [extruded at 180 C] conforms conforms 3.9 3.9 196 196 <2 <2 <10 <10 0.3 0.3 60 63 399 396 <20 <20 119,000 116,000 No change in chemical and physicochemical parameters up to 180 C Hot-Melt Extrusion Process Conditions Extrusion Studies Extrusion parameters 16mm ThermoFisher Polylab, 40D 200 rpm 1kg/h mean residence time ~1 min Extrusion temperature [ C] Polymer Itraconazole (15 %API) Fenofibrate (20 %API) Carbamazepine (15 %API) Soluplus 150 100 140 Extrusion lead to amorphous extrudates (XRD) in all cases 12
Soluplus Extrudates with Fenofibrate - Appearance dependent on drug load Soluplus + Fenofibrate 25% 30% 35% 40% 45% 50% The transparency of extrudates decreases with increasing Fenofibrate load Dissolution Extrudates with 15% Itraconazole drug release [%] 100 80 60 40 Soluplus Kollidon VA 64 Kollidon 12 PF HPC 20 0 0 30 60 90 120 t [min] USP apparatus 2, 50rpm, 700 ml HCL (0.1molar), granulated extrudates, 100mg API (n=3, mean±sd) Different matrix polymers give different dissolution profiles for Itraconazole 26 13
Soluplus Amorphous Extrudate XRD intensity [a.u.] crystalline itraconazole solid solution itraconazole 5 15 25 35 45 55 2 theta [ ] No crystalline active Solid solution Soluplus & itraconazole (85/15) Soluplus Bioavailability Enhancement of Itraconazole Plasma level [ng/ml] 750 600 Bioavailability of Soluplus extrudate: 26-fold compared to crystalline drug 2.3-fold compared to Sempera Bioavailability = area under the curve (AUC) 450 300 150 0 0 10 20 30 40 50 60 70 80 Time [hours] Itraconazole Soluplus extrudate Sempera Itraconazole crystalline A Soluplus solid solution significantly increases the bioavailability of Itraconazole 14
Hot-Melt Extrusion Manufacturing Process Strategy for Formulation Development Keep the formulation (and process) as simple as possible Active + Polymer Choose the appropriate polymer + Plasticizer For improved processability + Solubilizer For improved drug content and prevention of crystallization in gastric and intestinal fluid Summary Summary Melt extrusion is an excellent process to formulate poorly soluble drugs and to improve bioavailability Advantages vs spray drying continuous process Choice of an appropriate polymer is crucial for the formulation and the process Most important polymer features are -T g and melt viscosity - Solubilization capacity - Dissolution - Stability - Toxicity/regulatory status Polymers show very different extrusion behavior and suitability Interactions between the various ingredients strongly influence the formulation Soluplus is a highly promising excipient designed for solid solutions and hot-melt extrusion 15
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