The Role of Polymer Excipients in Hot Melt Extrusion A Continuous Manufacturing Process

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1 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

2 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

3 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), 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

4 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 C C prevents crystallization application of large amounts thermodynamically stable formulation 4

5 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 Kollicoat MAE 100 P Eudragit L 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

6 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 >50> Soluplus >50> Kollidon 12 PF Kollidon 17 PF <25< Kollidon 30 <25< < <25 >50> Kollidon 90 F <25< < <25 >50> Kollidon SR >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

7 Glass Transition Temperatures of matrix polymers Temperature [ C] Soluplus Kollidon 12PF Kollidon 90F Kollicoat MAE 130 HPC 186 Usually, extrusion requires temperatures of min 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

8 Melt Viscosities Melt Viscosity as a Function of Temperature Viscosity [Pas] 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 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

9 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 L0 extruded 160 C Kollidon VA 64 LT L0 0, M/Da Kollidon VA 64 can be extruded up to 220 C without degradation 9

10 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] Soluplus Pure API ~0.001 ~0.001 ~0.001 ~0.001 ~ ~ ~ % solubilizer solution, saturation solubility detected after 72h stirring Soluplus strongly increases the solubility for APIs with different chemical structures 10

11 Soluplus Saturation solubility in phosphate buffer ph 7.0 [g/100 ml] Soluplus Kolliphor RH40 Kolliphor PS 80 Kolliphor HS15 Kolliphor P % 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 C 1kg/h At extrusion temperatures up to 160 C nearly colourless extrudates 11

12 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 <2 < < <20 118,000 Extrudate Extrudate [extruded at 140 C] [extruded at 180 C] conforms conforms <2 <2 <10 < <20 <20 119, ,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 Extrusion lead to amorphous extrudates (XRD) in all cases 12

13 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 [%] Soluplus Kollidon VA 64 Kollidon 12 PF HPC 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

14 Soluplus Amorphous Extrudate XRD intensity [a.u.] crystalline itraconazole solid solution itraconazole theta [ ] No crystalline active Solid solution Soluplus & itraconazole (85/15) Soluplus Bioavailability Enhancement of Itraconazole Plasma level [ng/ml] Bioavailability of Soluplus extrudate: 26-fold compared to crystalline drug 2.3-fold compared to Sempera Bioavailability = area under the curve (AUC) Time [hours] Itraconazole Soluplus extrudate Sempera Itraconazole crystalline A Soluplus solid solution significantly increases the bioavailability of Itraconazole 14

15 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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