The document discusses hot melt extrusion for amorphous formulations. It summarizes that about 40% of new APIs have poor solubility and are classified as Class II or IV in the Biopharmaceutical Classification System. Hot melt extrusion is presented as a continuous process that can transform crystalline drugs into amorphous forms through melting and mixing with polymers without using solvents. The document reviews the processing, performance, stability, and analytical characterization of drug-polymer hot melt extrudates using solubility parameters, thermal analysis, rheology, dissolution testing, and other techniques. It finds that hot melt extrusion improves drug dissolution by creating amorphous solid dispersions and that performance depends on drug-polymer interactions and pH conditions.

1. Hot Melt Extrusion for Amorphous Formulations
Ashish Sarode

2. Outline
• Introduction
• Processing
• Performance
• Stability
• Summary

3. Introduction
• Biopharmaceutical Classification System (BCS)
High Solubility Low Solubility
High permeability Class I Class II
Low permeability Class III Class IV
• High throughput screening is resulting in more complex API structures
with an increase in Class II and Class IV APIs.
• About 40 % of all new APIs fail in development due to their poor solubility.
• There is a trend for recent drug candidates to be in Class II.

4. Introduction
• Class II and Class IV APIs
• Crystalline Hydrophobic Compounds
Crystalline Amorphous

5. Introduction
• Process • Advantages
– API, Thermoplastic Polymers – Continuous Process
– Heating, Melting-Softening, Mixing – Absence of Solvents
– Extrusion (Cylinders, Films) – No Drying Step
– Amorphous Transformation
– Cooling (On the Conveyor)
– Solid Solutions
– Plasticizers, Surfactants, Antioxidants
– Interactions

6. Introduction
• Hot Melt Extrusion (Aspects) • Hot Melt Extrusion (Analytical Techniques)
– Processing – Solubility Parameters
• Miscibility – Thermal Analysis (DSC)
• Temperature – Rheological Evaluation
• Speed – X-Ray Diffraction
– Characteristics – Polarized Light Microscopy
• Solid Solution – IR Spectroscopy
• Amorphous
– Dissolution Study
• Intermolecular Interactions
– Performance
• Dissolution Rate
• Supersaturation
– Stability
• Characteristics
• Performance

7. Processing (Materials)
• APIs (Model Drugs) • Hydrophilic Polymers
– Indomethacin (IND) (Tm = 162°C) – Eudragit EPO (Tg = 50°C)
– Itraconazole (ITZ) (Tm = 165°C) – Eudragit L-100-55 (Tg = 110°C)
– Griseofulvin (GSF) (Tm = 220°C) – Eudragit L-100 (Tg = 150°C)
– HPMCAS-LF (Tg = 120°C)
– HPMCAS-MF (Tg = 120°C)
– Pharmacoat 603 (Tg = 156°C)
– Kollidon VA-64 (Tg = 107°C)

8. Processing (Methods)
• Solubility Parameter Calculations
– ChemSW Software, Chemical Structures, Van Krevelen and Hoftyzer’s Group Contribution Method
• Preparation of Physical Mixtures
– Drug : Polymer (30:70, 50:50, 70:30) Ratios
– Mortar and Pestle, Amber Glass Bottles, Turbula Mixer
• Thermal Analysis
– 6-8 mg Sample, Heat-Cool-Heat Cycle, Heating Rate 10°C/min, Cooling Rate 50ºC/min, Melting Point,
Glass Transition Temperature
• Rheological Evaluation
– Softening Temperatures, 20mm Steel Plate Geometry, Sample Thickness 1mm, Zero Rate Viscosity using
Cross Model
• Hot Melt Extrusion
– Haake MiniLab Microcompounder, Manual Feeding, Temperature and Speed (Thermal and Rheological
Evaluation), Extrudates – Milled, Screened, Stored in Desiccators

9. Processing (Solubility Parameters)
Prediction of immiscibility between ITZ and Eudragit EPO due to higher ∆δ

10. Processing (Thermal Analysis)
Immiscibility between ITZ and Eudragit EPO was confirmed

11. Processing (Thermal Analysis) ITZ
• Disobeying of Gordan-Taylor equation could
be due to counter-ionic interaction between
IND and Eudragit EPO
IND
GSF

12. Processing (Rheological Evaluation)
IND : Eudragit EPO ITZ : Eudragit L-100-55

13. Processing (Rheological Evaluation)
Comparison of softening temperatures of PMs Comparison of η0 at same softening temperatures
IND (100 rpm), ITZ (150 rpm), and GSF (200 rpm) at their softening temperatures

14. Processing (Rheological Evaluation)
η0 was dependent on the concentration and state of the drug in the PMs at the softening temperatures
IND GSF
ITZ ITZ

15. Processing (Hot Melt Extrusion)

16. Processing (Hot Melt Extrusion)

17. Processing (Hot Melt Extrusion)

18. Processing (Summary)
• Solubility Parameters
– Prediction of immiscibility between ITZ and Eudragit EPO
• Thermal Analysis
– Confirmation of immiscibility between ITZ and Eudragit EPO
– Prediction of physical state of the extrudates
– Exceptions to Gordon Taylor equation – stronger counter-ionic interactions (IND : Eudragit EPO)
• Rheological Evaluation
– Estimation of processing conditions for HME – softening temperatures and zero rate viscosity
• Hot Melt Extrusion
– Transparent glassy HMEs (Solid Solutions)

19. Performance (Materials)
• APIs (Model Drugs) • Hydrophilic Polymers
– Indomethacin (IND) (Weak Acid) – Eudragit EPO (Cationic)
– Itraconazole (ITZ) (Weak Base) – Eudragit L-100-55 (Anionic)
– Griseofulvin (GSF) (Neutral) – Eudragit L-100 (Anionic)
– HPMCAS-LF (Anionic)
– HPMCAS-MF (Anionic)
– Pharmacoat 603 (Non-ionic)
– Kollidon VA-64 (Non-ionic)

20. Performance (Materials)

21. Performance (Materials)

22. Performance (Materials)
IND ITZ
pH Dependent Ionization pH Dependent Ionization
100
100
80
80
% Ionized
% Ionized
60
60
40
40
20
20
0
0 2 4 6 8 10 12 14
0
0 2 4 6 8 10 12 14 pH
pH
Itraconazole ITZ pKa
Indomethacin IND pKa
Prediction of dissolution improvement in unfavorable pH conditions due to counter-ionic interactions

23. Performance (Methods)
• Powder X-Ray Diffraction (PXRD)
– PMs, and Milled HMEs, Cu K α Radiation, Angular Range of 1 < 2θ < 40°, Step Width 0.02°, Scan
Rate 1°/ per minute
• Polarized Light Microscopy (PLM)
– Light Intensity 5.0, Magnification 10X
– PMs & Milled HMEs in Mineral Oil, and Milled HMEs in Dissolution Medium
• FT-IR Spectroscopy
– Smart Orbit Accessory, Nicolet Nexus FT-IR, Omnic Software
– PMs of crystalline and amorphous APIs with the polymers, Milled HMEs
• Dissolution Study
– PMs and Milled HMEs
– USP Dissolution Apparatus II, 0.1N HCl (SGF), Phosphate Buffer pH 6.8 (SIF), 37°C, 50rpm
– IND (Tablets, 320nm), ITZ (Powder, 263nm), and GSF (Powder, 293nm)

24. Performance (PXRD)
Amorphous transformation due to HME

25. Performance (PXRD)
Amorphous transformation due to HME

26. Performance (PLM)
No surface crystallization because of the dissolution medium

27. Performance (FT-IR Spectroscopy) (IND and ITZ)

28. Performance (FT-IR Spectroscopy) (GSF)
• Intermolecular interactions between the
drugs and the polymers during HME
• Not possible to distinguish the stronger
counter-ionic interactions

29. Performance (Dissolution Study – IND)
Only counter-ionic polymer improved the dissolution of IND in SGF

30. Performance (Dissolution Study – ITZ)
Only counter-ionic polymers improved the dissolution of ITZ in SIF

31. Performance (Dissolution Study)
Dissolution of GSF was improved in both SGF and SIF using all the polymers

32. Performance (Summary)
• PXRD Analysis
– Amorphous transformation due to HME
– Amorphous transformation – Independent of API concentration
• PLM
– No surface crystallization of APIs on the HMEs due to dissolution medium
– No reduction in dissolution due to surface crystallization
• FTIR Spectroscopy
– Intermolecular interactions between the drugs and the polymers during HME
– Not possible to distinguish the stronger counter-ionic interactions
• Dissolution Study
– Dissolution of all the drugs was improved using HME technology
– Improvement was dependent on pH dependent ionization and drug-polymer interactions for IND and ITZ than
merely amorphous transformation
– Improvement was dependent on both amorphous transformation and drug-polymer interactions for GSF

33. Stability (Materials)
• Formulations
– IND : Eudragit EPO (30:70)
– IND : Kollidon VA-64 (30:70)
– ITZ : HPMCAS-LF (30:70)
– ITZ : Kollidon VA-64 (30:70)

34. Stability (Methods)
• Hot Melt Extrusion • Moisture Analysis
– Leistritz Hot Melt Extruder Micro-18 Model, Four – Los on Drying (LOD), Pre-weighed Aluminium Pans,
Barrels, Conveying Elements, Co-Rotating Twin- % Weight Loss, % Moisture Content
Screws, 400g PM, 15g/min, Extrudates – Milled,
Screened, Stored in Desiccator at 5°C • Thermal Analysis
– 6-8 mg Sample, Heat-Cool-Heat Cycle, Heating Rate
• Stability Chambers 10°C/min, Cooling Rate 50ºC/min, Melting Point,
– Saturated Salt Solutions, Closed Porous Plastic Glass Transition Temperature
Containers, Analysis – 1, 3, 6, 9, 12 Weeks
• Powder X-Ray Diffraction (PXRD)
– Milled HMEs, Cu K α Radiation, Angular Range of 1
< 2θ < 40°, Step Width 0.02°, Scan Rate 1°/ per
minute
• Dissolution Study
– USP Dissolution Apparatus II, 0.1N HCl (SGF),
Phosphate Buffer pH 6.8 (SIF), 37°C, 50rpm
– IND (265nm), and ITZ (263nm)

35. Stability (Hot Melt Extrudates)
• Four barrel system of Leistritz extruder with
all the conveying elements of co-rotating
twin screws simulated well with the design
of Mini-Lab MicroCompounder
• Transparent glassy HMEs could be produced
using temperatures and speeds estimated in
part I

36. Stability (Moisture Analysis)
(a) IND : Eudragit EPO
10
Moisture Content (%w/w)
8
6
4
2
0
1 Week
1 Week
1 Week
1 Week
1 Week
1 Week
1 Week
1 Week
1 Week
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
34% RH 76% RH 96% RH 33% RH 75% RH 97% RH 31% RH 74% RH 96% RH
Initial 5°C 25°C 50°C
Stability Conditions
Moisture content was increased with temperature and humidity over time

37. Stability (Moisture Analysis)
(b) IND : Kollidon VA-64
10
8
Moisture Content (%w/w)
6
4
2
0
1 Week
1 Week
1 Week
1 Week
1 Week
1 Week
1 Week
1 Week
1 Week
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
34% RH 76% RH 96% RH 33% RH 75% RH 97% RH 31% RH 74% RH 96% RH
Initial 5°C 25°C 50°C
Stability Conditions
Moisture content was increased with temperature and humidity over time

38. Stability (Moisture Analysis)
(a) ITZ : HPMCAS-LF
6
Moisture Content (%w/w)
4
2
0
1 Week
1 Week
1 Week
1 Week
1 Week
1 Week
1 Week
1 Week
1 Week
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
34% RH 76% RH 96% RH 33% RH 75% RH 97% RH 31% RH 74% RH 96% RH
Initial 5°C 25°C 50°C
Stability Conditions
Moisture content was increased with temperature and humidity over time

39. Stability (Moisture Analysis)
(b) ITZ : Kollidon VA-64
15
12
Moisture Content (%w/w)
9
6
3
0
1 Week
1 Week
1 Week
1 Week
1 Week
1 Week
1 Week
1 Week
1 Week
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
3
6
9
12
34% RH 76% RH 96% RH 33% RH 75% RH 97% RH 31% RH 74% RH 96% RH
Initial 5°C 25°C 50°C
Stability Conditions
Prediction of instability of ITZ : Kollidon VA-64 HMEs due to higher moisture content

40. Stability (Thermal Analysis)
(a) IND:Eudragit EPO (b) IND:Kollidon VA-64
100 100
Glass Transition Temperature
Glass Transition Temperature
80 80
60 60
40 40
20 20
0 0
34%
76%
96%
33%
75%
97%
31%
74%
96%
34%
76%
96%
33%
75%
97%
31%
74%
96%
34%
76%
96%
33%
75%
97%
31%
74%
96%
34%
76%
96%
33%
75%
97%
31%
74%
96%
34%
76%
96%
33%
75%
97%
31%
74%
96%
34%
76%
96%
33%
75%
97%
31%
74%
96%
34%
76%
96%
33%
75%
97%
31%
74%
96%
34%
76%
96%
33%
75%
97%
31%
74%
96%
34%
76%
96%
33%
75%
97%
31%
74%
96%
34%
76%
96%
33%
75%
97%
31%
74%
96%
5°C 25°C 50°C 5°C 25°C 50°C 5°C 25°C 50°C 5°C 25°C 50°C 5°C 25°C 50°C 5°C 25°C 50°C 5°C 25°C 50°C 5°C 25°C 50°C 5°C 25°C 50°C 5°C 25°C 50°C
Initial 1 Week 3 Weeks 6 Weeks 9 Weeks 12 Weeks Initial 1 Week 3 Weeks 6 Weeks 9 Weeks 12 Weeks
Stability Conditions Stability Conditions
(a) ITZ:HPMCAS-LF (b) ITZ:Kollidon VA-64
100 100
Glass Transition Temperature
Glass Transition Temperature
80 80
60 60
40 40
20 20
0 0
34%
76%
96%
33%
75%
97%
31%
74%
96%
34%
76%
96%
33%
75%
97%
31%
74%
96%
34%
76%
96%
33%
75%
97%
31%
74%
96%
34%
76%
96%
33%
75%
97%
31%
74%
96%
34%
76%
96%
33%
75%
97%
31%
74%
96%
34%
76%
96%
33%
75%
97%
31%
74%
96%
34%
76%
96%
33%
75%
97%
31%
74%
96%
34%
76%
96%
33%
75%
97%
31%
74%
96%
34%
76%
96%
33%
75%
97%
31%
74%
96%
34%
76%
96%
33%
75%
97%
31%
74%
96%
5°C 25°C 50°C 5°C 25°C 50°C 5°C 25°C 50°C 5°C 25°C 50°C 5°C 25°C 50°C 5°C 25°C 50°C 5°C 25°C 50°C 5°C 25°C 50°C 5°C 25°C 50°C 5°C 25°C 50°C
Initial 1 Week 3 Weeks 6 Weeks 9 Weeks 12 Weeks Initial 1 Week 3 Weeks 6 Weeks 9 Weeks 12 Weeks
Stability Conditions Stability Conditions
Prediction of instability of IND : Eudragit EPO due to lower Tg

41. Stability (Thermal Analysis)
Prediction of ITZ crystallization at 50°C, 74%RH and 96%RH after 6 weeks

42. Stability (Thermal Analysis)
Prediction of ITZ crystallization at 50°C, 96%RH due to phase separation

43. Stability (Powder X-Ray Diffraction)
Prediction of reduction in ITZ dissolution for stability samples with crystallization

44. Stability (Dissolution Study – IND : Kollidon VA-64)
31-34% RH 74-76% RH 96-97% RH
5°C
25°C
50°C

45. Stability (Dissolution Study – ITZ : Kollidon VA-64)
31-34% RH 74-76% RH 96-97% RH
5°C
25°C
50°C

46. Stability (Dissolution Study – ITZ : HPMCAS-LF)
31-34% RH 74-76% RH 96-97% RH
5°C
25°C
50°C

47. Stability (Dissolution Study – IND : Eudragit EPO)
31-34% RH 74-76% RH 96-97% RH
5°C
25°C
50°C

48. Stability (Dissolution Study – IND : Eudragit EPO)
Possible increase in counter-ionic interactions with the increase in temperature and humidity over time

49. Stability (Summary)
• Hot Melt Extrusion
– Possible to predict feasibility of HME production at large scale by simulating designs of the extruders
• Moisture Analysis
– Moisture content increased with time, temperature, and humidity
– The hygroscopicity of vinyl polymer was higher than that of methacrylic and cellulosic polymers
• Thermal Analysis
– Amorphous ITZ was physically unstable at higher temperatures and humidity levels
– The crystallization and phase separation of ITZ could be determined using DSC
• Powder X-Ray Diffraction
– Crystallization of ITZ could be confirmed
• Dissolution Study
– Dissolution of ITZ was reduced for stability samples with crystallization
– Dissolution of IND was reduced for stability samples with chemical degradation
– Supersaturation of ITZ and IND was improved over stability period for HMEs with polymers counter-ionic to these drugs

50. Exciting Discovery
• Drug-Polymer interactions play an important role in
– Processing HME product
– Improving dissolution rate
– Enhancing supersaturation levels
• The supersaturation of ionic drugs was improved in unfavorable pH conditions possibly due to
improvement in counter-ionic interactions with the polymers
• These counter-ionic interactions could have been increased due to water assisted charge transfer
• The controlled use of temperature and moisture could be beneficial to improve the intermolecular
interactions to sustain the supersaturation levels

51. Acknowledgements
• Dr. Hossein Zia
• Dr. Harpreet Sandhu
• Dr. Navnit Shah
• Dr. Waseem Malick
• Mr. Bharat Patel
• Committee Members
• Family and Friends