Starch melts as solvents for pharmaceutical drugs
Topics Extrusion Analytic Glass transition temperature Crystallinity Dissolution Scanning electron microscopy Summary
Starch in pharmacy Disintegrator in tablets Gel former Binder Raw material for polymer matrices
Extrusion The single screw extruder feeding melting and kneading forming
Brabender single screw extruder Hopper with plug screw Gear Die Engine Nozzle (5mm) Barrel Tubes for the water/glycol tempering
Production process of the extrudates 1. Mixing starch and water (placebo) and drug (solid solution) 2. Melt extrusion of the compound 3. Simultaneous measurement of the torque and the extrusion speed (measurement frequency : 5 Hz)
Extruder settings Temperature profile: Feeding section: 66 C Barrel: 85 C Die: 98 C Screw rotation speed: 100 rpm Nozzle diameter: 5 mm
Results: Starch-placebo extrudates Corn Peas Potato Eurylon 5 Waxilys 200
Characteristics of the placebo extrudates Starch Batch Dieswelling Extrusion speed [g/min] Extrusion speed [cm/min] SME [kj/kg] TG [ C] Corn 271004a 1,32 20,6 40 210 98 Peas 150205a 1,44 23,1 39 335 85 Potato 280205d 1,50 62,2 105 163 88 Eurylon 5 040405d 1,00 27,3 100 420 93 Waxilys 200 080405c 1,20 15,7 44 250 88 SME: specific mechanical energy: average torque / extrudated mass TG: glass transition temperature (DMA)
Tramadol-HCl: Strong analgetic (e.g. Tramadolor 100 Retard-Tabletten) Melting point: 180 184 C Water solubility (1 : 1) important for producing solid solutions with starch/water UV detectable
Results: Starch-Tramadol-HCl extrudates (Drug content 10 %) Corn Peas Potato Eurylon 5 Waxilys 200
Characteristics of the Tramadol-HCl extrudates Starch Batch Dieswelling Extrusion speed [g/min] Extrusion speed [cm/min] SME [kj/kg] TG [ C] Corn 230805a 1,04 10,9 35 177 70 Peas 250805c 1,14 13,9 38 328 68 Potato 250805e 1,20 13,3 34 122 68 Eurylon 5 240805c 1,00 12,7 44 168 71 Waxilys 200 250805a 1,04 13,4 47 136 73 SME: specific mechanical energy: average torque / extrudated mass TG: glass transition temperature (DMA)
Analytic Glass transition temperature Glassy state (T < Tg): Hard and brittle Amorphous solid with immobile molecules The molecules may be able to vibrate slightly Rubbery state (T > Tg) : Soft and flexible Amorphous solid in which the molecules can rotate freely Dissolution speed increased Tg: Temperature at which the polymer changes from glassy state into the rubbery state.
Dynamic mechanical analysis (DMA) DIN 61006 Planparallel sample held between two parallel plates Sinusoidal oscillation force to the probe Static force : 10 N Dynamic force : 2 N Frequency: 1 Hz Temperature range: 20 C 140 C Temperature gradient : 1 C/min Upper plate Lower plate Sample Oven with ventilator The DMA module measures changes in the vicoelastic properties of the material resulting from changes in the temperature.
Analytic : DMA signal of placebo extrudate E' [MPa] Eurylon5-placebo extrudate batch 040405d 700 600 500 400 300 200 100 0 20 30 40 50 60 70 80 90 100 110 120 130 Temperature [ C] 0,08 0,07 0,06 0,05 0,04 0,03 0,02 0,01 0 tan E : Storage modulus: (represents the solid part of the material) tan : Loss factor : It is a measure of energy lost during one loading cycle. maximum = glass transition temperature Tg placebo: 93 C
Analytic: DMA signal of Tramadol-extrudate Eurylon5-Tramadol-HCl-extrudate batch 240805c E' [MPa] 1800 1600 1400 1200 1000 800 600 400 200 0 20 30 40 50 60 70 80 90 100 110 120 130 Temperature [ C] 0,18 0,16 0,14 0,12 0,1 0,08 0,06 0,04 0,02 0 tan Maximum tan δ at 71 C The Tg of the Tramadol-HCl extrudate is lower than the Tg of the placebo The drug is a plasticizer for the polymer
Degree of crystallinity X-ray diffractometry: Tramadol-HCl-potato-starch extrudate The starch and drug shows a signal for crystalline substances The Tramadol extrudate shows a typical halo for amorphous materials
Dissolution (paddel, Ph. Eur.) Samples: 300 mg extrudate (30 mg Tramdol-HCl) Dissolution medium: A: 0.1 N HCl, B: phosphate buffer ph 6.8 Dissolution conditions: 50 rpm, 37 C Before dissolution After dissolution Potato-Tramadol-HCl-extrudates batch 250805e
Results of the dissolution study Release profile of Tramadol-HCl Dissolution of Tramadol-HCl using different starches as polymeric carrier Drug release [%] 110 100 90 80 70 10 % Tramadol-HCl, peas, 0.1 N HCl 60 10 % Tramadol-HCl, peas, phosphate buffer ph 6.8 50 10 % Tramadol-HCl, potato, 0.1 N HCl 40 30 10 % Tramadol-HCl, potato, phosphate buffer ph 6.8 20 10 % Tramadol-HCl, w axilys 200, 0.1 N HCl 10 10 % Tramadol-HCl, w axilys 200, phosphate buffer ph 6.8 0 0 5 10 15 20 25 30 time [h] Matrices that contained waxy corn starch allowed to release the drug in a shorter time period (10-12 h). Potato starch released the drug in a longer time period (22-24 h). higher retardation effekt of potato starch
Scanning electron microscopy raw materials and placebo extrudate Potato starch + 10 % Tramadol-HCl (x 300) Potato starch placebo extrudate (x 40)
Potato-starch-Tramadol-HCl-extrudate Before dissolution After 24 h dissolution x 40 x 40 x 400 x 400
Summary The production of solid solution requires: Starch (e.g. potato starch) Water (plasticizer) Water solible drug Temperature above the gelatinisation temperature Specific mechanical energy of 100 350 kj/kg Influence of Tramadol The drug acts as a platicizer to the polymer SME and Tg reduces significantly Waxilys 200 lowest retardation effect Potato starch highest retardation effect
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