Starch melts as solvents for pharmaceutical drugs. Gabriel Wauer / Hubert Rein

Transcription

1 Starch melts as solvents for pharmaceutical drugs

2 Topics Extrusion Analytic Glass transition temperature Crystallinity Dissolution Scanning electron microscopy Summary

3 Starch in pharmacy Disintegrator in tablets Gel former Binder Raw material for polymer matrices

4 Extrusion The single screw extruder feeding melting and kneading forming

5 Brabender single screw extruder Hopper with plug screw Gear Die Engine Nozzle (5mm) Barrel Tubes for the water/glycol tempering

6 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)

7 Extruder settings Temperature profile: Feeding section: 66 C Barrel: 85 C Die: 98 C Screw rotation speed: 100 rpm Nozzle diameter: 5 mm

8 Results: Starch-placebo extrudates Corn Peas Potato Eurylon 5 Waxilys 200

9 Characteristics of the placebo extrudates Starch Batch Dieswelling Extrusion speed [g/min] Extrusion speed [cm/min] SME [kj/kg] TG [ C] Corn a 1,32 20, Peas a 1,44 23, Potato d 1,50 62, Eurylon d 1,00 27, Waxilys c 1,20 15, SME: specific mechanical energy: average torque / extrudated mass TG: glass transition temperature (DMA)

10 Tramadol-HCl: Strong analgetic (e.g. Tramadolor 100 Retard-Tabletten) Melting point: C Water solubility (1 : 1) important for producing solid solutions with starch/water UV detectable

11 Results: Starch-Tramadol-HCl extrudates (Drug content 10 %) Corn Peas Potato Eurylon 5 Waxilys 200

12 Characteristics of the Tramadol-HCl extrudates Starch Batch Dieswelling Extrusion speed [g/min] Extrusion speed [cm/min] SME [kj/kg] TG [ C] Corn a 1,04 10, Peas c 1,14 13, Potato e 1,20 13, Eurylon c 1,00 12, Waxilys a 1,04 13, SME: specific mechanical energy: average torque / extrudated mass TG: glass transition temperature (DMA)

13 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.

14 Dynamic mechanical analysis (DMA) DIN 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.

15 Analytic : DMA signal of placebo extrudate E' [MPa] Eurylon5-placebo extrudate batch d 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

16 Analytic: DMA signal of Tramadol-extrudate Eurylon5-Tramadol-HCl-extrudate batch c E' [MPa] 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

17 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

18 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 e

19 Results of the dissolution study Release profile of Tramadol-HCl Dissolution of Tramadol-HCl using different starches as polymeric carrier Drug release [%] % Tramadol-HCl, peas, 0.1 N HCl % Tramadol-HCl, peas, phosphate buffer ph % Tramadol-HCl, potato, 0.1 N HCl % Tramadol-HCl, potato, phosphate buffer ph % Tramadol-HCl, w axilys 200, 0.1 N HCl % Tramadol-HCl, w axilys 200, phosphate buffer ph 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

20 Scanning electron microscopy raw materials and placebo extrudate Potato starch + 10 % Tramadol-HCl (x 300) Potato starch placebo extrudate (x 40)

21 Potato-starch-Tramadol-HCl-extrudate Before dissolution After 24 h dissolution x 40 x 40 x 400 x 400

22 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 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

23 Thank You for Your Attention!

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