Hot Melt Extrusion for Amorphous Formulations

Ashish Sarode

Outline

• Introduction

• Processing

• Performance

• Stability

• Summary

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.

Introduction

• Class II and Class IV APIs

• Crystalline Hydrophobic Compounds

Crystalline Amorphous

Introduction

• Process

– API, Thermoplastic Polymers

– Heating, Melting-Softening, Mixing

– Extrusion (Cylinders, Films)

– Cooling (On the Conveyor)

– Plasticizers, Surfactants, Antioxidants

• Advantages

– Continuous Process

– Absence of Solvents

– No Drying Step

– Amorphous Transformation

– Solid Solutions

– Interactions

Introduction

• Hot Melt Extrusion (Aspects)

– Processing• Miscibility• Temperature• Speed

– Characteristics• Solid Solution• Amorphous• Intermolecular Interactions

– Performance• Dissolution Rate• Supersaturation

– Stability• Characteristics• Performance

• Hot Melt Extrusion (Analytical Techniques)

– Solubility Parameters

– Thermal Analysis (DSC)

– Rheological Evaluation

– X-Ray Diffraction

– Polarized Light Microscopy

– IR Spectroscopy

– Dissolution Study

Processing (Materials)

• APIs (Model Drugs)

– Indomethacin (IND) (Tm = 162°C)

– Itraconazole (ITZ) (Tm = 165°C)

– Griseofulvin (GSF) (Tm = 220°C)

• Hydrophilic Polymers

– Eudragit EPO (Tg = 50°C)

– Eudragit L-100-55 (Tg = 110°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)

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

Processing (Solubility Parameters)

Prediction of immiscibility between ITZ and Eudragit EPO due to higher ∆δ

Processing (Thermal Analysis)

Immiscibility between ITZ and Eudragit EPO was confirmed

Processing (Thermal Analysis)

• Disobeying of Gordan-Taylor equation could be due to counter-ionic interaction between IND and Eudragit EPO

IND

ITZ

GSF

Processing (Rheological Evaluation)

ITZ : Eudragit L-100-55IND : Eudragit EPO

Processing (Rheological Evaluation)

IND (100 rpm), ITZ (150 rpm), and GSF (200 rpm) at their softening temperatures

Comparison of softening temperatures of PMs Comparison of η0 at same softening temperatures

Processing (Rheological Evaluation)

η0 was dependent on the concentration and state of the drug in the PMs at the softening temperatures

IND GSF

ITZITZ

Processing (Hot Melt Extrusion)

Processing (Hot Melt Extrusion)

Processing (Hot Melt Extrusion)

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)

Performance (Materials)

• APIs (Model Drugs)

– Indomethacin (IND) (Weak Acid)

– Itraconazole (ITZ) (Weak Base)

– Griseofulvin (GSF) (Neutral)

• Hydrophilic Polymers

– Eudragit EPO (Cationic)

– Eudragit L-100-55 (Anionic)

– Eudragit L-100 (Anionic)

– HPMCAS-LF (Anionic)

– HPMCAS-MF (Anionic)

– Pharmacoat 603 (Non-ionic)

– Kollidon VA-64 (Non-ionic)

Performance (Materials)

Performance (Materials)

Performance (Materials)

IND ITZ

Prediction of dissolution improvement in unfavorable pH conditions due to counter-ionic interactions

0

20

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80

100

0 2 4 6 8 10 12 14

% Io

niz

ed

pH

pH Dependent Ionization

Indomethacin IND pKa

0

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80

100

0 2 4 6 8 10 12 14

% Io

niz

ed

pH

pH Dependent Ionization

Itraconazole ITZ pKa

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)

Performance (PXRD)

Amorphous transformation due to HME

Performance (PXRD)

Amorphous transformation due to HME

Performance (PLM)

No surface crystallization because of the dissolution medium

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

Performance (FT-IR Spectroscopy) (GSF)

• Intermolecular interactions between the drugs and the polymers during HME

• Not possible to distinguish the stronger counter-ionic interactions

Performance (Dissolution Study – IND)

Only counter-ionic polymer improved the dissolution of IND in SGF

Performance (Dissolution Study – ITZ)

Only counter-ionic polymers improved the dissolution of ITZ in SIF

Performance (Dissolution Study)

Dissolution of GSF was improved in both SGF and SIF using all the polymers

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

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)

Stability (Methods)

• Hot Melt Extrusion

– Leistritz Hot Melt Extruder Micro-18 Model, Four Barrels, Conveying Elements, Co-Rotating Twin-Screws, 400g PM, 15g/min, Extrudates – Milled, Screened, Stored in Desiccator at 5°C

• Stability Chambers

– Saturated Salt Solutions, Closed Porous Plastic Containers, Analysis – 1, 3, 6, 9, 12 Weeks

• Moisture Analysis

– Los on Drying (LOD), Pre-weighed Aluminium Pans, % Weight Loss, % Moisture Content

• Thermal Analysis

– 6-8 mg Sample, Heat-Cool-Heat Cycle, Heating Rate 10°C/min, Cooling Rate 50ºC/min, Melting Point, Glass Transition Temperature

• 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)

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

Stability (Moisture Analysis)

Moisture content was increased with temperature and humidity over time

(a) IND : Eudragit EPO

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1 W

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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

Mo

istu

re C

on

ten

t (%

w/w

)

Stability (Moisture Analysis)

Moisture content was increased with temperature and humidity over time

(b) IND : Kollidon VA-64

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k 3 6 9

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1 W

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k 3 6 9

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1 W

ee

k 3 6 9

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1 W

ee

k 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

Mo

istu

re C

on

ten

t (%

w/w

)

Stability (Moisture Analysis)

Moisture content was increased with temperature and humidity over time

(a) ITZ : HPMCAS-LF

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1 W

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1 W

eek 3 6 9

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1 W

eek 3 6 9

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1 W

eek 3 6 9

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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

Mo

istu

re C

on

ten

t (%

w/w

)

Stability (Moisture Analysis)

Prediction of instability of ITZ : Kollidon VA-64 HMEs due to higher moisture content

(b) ITZ : Kollidon VA-64

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1 W

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1 W

eek 3 6 9

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1 W

eek 3 6 9

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1 W

eek 3 6 9

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1 W

eek 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

Mo

istu

re C

on

ten

t (%

w/w

)

Stability (Thermal Analysis)(a) IND:Eudragit EPO

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34%

76%

96%

33%

75%

97%

31%

74%

96%

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97%

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74%

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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

Initial 1 Week 3 Weeks 6 Weeks 9 Weeks 12 Weeks

Stability Conditions

Gla

ss T

ran

sit

ion

Te

mp

era

ture

(b) IND:Kollidon VA-64

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34%

76%

96%

33%

75%

97%

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34%

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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

Initial 1 Week 3 Weeks 6 Weeks 9 Weeks 12 Weeks

Stability Conditions

Gla

ss

Tra

nsit

ion

Te

mp

era

ture

(a) ITZ:HPMCAS-LF

0

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100

34%

76%

96%

33%

75%

97%

31%

74%

96%

34%

76%

96%

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97%

31%

74%

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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

Initial 1 Week 3 Weeks 6 Weeks 9 Weeks 12 Weeks

Stability Conditions

Gla

ss T

ran

sit

ion

Te

mp

era

ture

(b) ITZ:Kollidon VA-64

0

20

40

60

80

100

34%

76%

96%

33%

75%

97%

31%

74%

96%

34%

76%

96%

33%

75%

97%

31%

74%

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31%

74%

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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

Initial 1 Week 3 Weeks 6 Weeks 9 Weeks 12 Weeks

Stability Conditions

Gla

ss T

ran

sit

ion

Te

mp

era

ture

Prediction of instability of IND : Eudragit EPO due to lower Tg

Stability (Thermal Analysis)

Prediction of ITZ crystallization at 50°C, 74%RH and 96%RH after 6 weeks

Stability (Thermal Analysis)

Prediction of ITZ crystallization at 50°C, 96%RH due to phase separation

Stability (Powder X-Ray Diffraction)

Prediction of reduction in ITZ dissolution for stability samples with crystallization

Stability (Dissolution Study – IND : Kollidon VA-64)

5°C

25°C

50°C

31-34% RH 74-76% RH 96-97% RH

Stability (Dissolution Study – ITZ : Kollidon VA-64)

5°C

25°C

50°C

31-34% RH 74-76% RH 96-97% RH

Stability (Dissolution Study – ITZ : HPMCAS-LF)

5°C

25°C

50°C

31-34% RH 74-76% RH 96-97% RH

Stability (Dissolution Study – IND : Eudragit EPO)

5°C

25°C

50°C

31-34% RH 74-76% RH 96-97% RH

Stability (Dissolution Study – IND : Eudragit EPO)

Possible increase in counter-ionic interactions with the increase in temperature and humidity over time

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

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

Acknowledgements

• Dr. Hossein Zia

• Dr. Harpreet Sandhu

• Dr. Navnit Shah

• Dr. Waseem Malick

• Mr. Bharat Patel

• Committee Members

• Family and Friends