pharmaceutical melt extrusion and tabletting aps … · pharmaceutical melt extrusion and...

Pharmaceutical Melt Extrusion and Tabletting

Ian Gabbott Drug Product Development, Pharmaceutical Development UK

APS Amorphous by Design

Formulation and process selection

Formulations containing crystalline poorly soluble drug substance are possible but must contain a low drug load to be bio-available.

Therefore, large number of dosage units required to achieve therapeutic dose.

In the development of one of our compounds, alternative formulations and dosage forms were investigated, including 74 solid dispersion formulations!

Crystalline versus amorphous

2 Ian Gabbott, Drug Product Development | 2014 Global Medicines Development | Pharmaceutical Development

Crystalline drug substance Amorphous drug substance

Immediate release tablet Solid dispersion in capsules

Micro-suspension Solid dispersion in tablets

Nano-suspension

Lipid matrix technologies

Formulation and process selection

Conventional immediate release tablet

Formulation and manufacturing

• 25% w/w drug substance

• Common immediate release tablet diluents, disintegrant and lubricant

• Manufactured by direct compression

Results

• Formulations were stable

• Dissolution tests showed acceptable release

• In-vivo performance was poor

Formulations containing crystalline drug


Formulation and process selection Formulations containing crystalline drug

Nano-suspension


• 1% w/w drug substance

• Carrier (HPMC/Tween)

• Ball milled

• Filled into capsules

Results

• Stability data showed that all 3 were acceptable

• Dissolution data showed better performance for nano-suspension formulations than for drug alone

• Very low drug loading and poor in-vivo performance


Formulation and process selection Formulations containing crystalline drug

Lipid matrix


• Drug substance (10-40% w/w)

• Lipid (lauroyl macrogolglyceride, identified from a preliminary solubilisation excipient screen)

• HPMC capsule filling

Results

Stability data showed that formulations were stable

Dissolution performance showed acceptable release

However, trade-off between drug load and in-vivo performance


Formulation and process selection Theoretical benefits of amorphous drug

According to Hamlin, Intrinsic Dissolution Rate (IDR) is related to drug solubility by the formula:

IDR = 2.24 x solubility

The IDR for crystalline drug correlates well to the measured solubility; on this basis the predicted solubility for the amorphous has been estimated.

Based on these predictions, the amorphous form could show a 40 fold increase in kinetic solubility relative to crystalline drug.

But, designing a stable formulation of a drug in the amorphous form is challenging

According to the paper by Yu, amorphous drug would be classified as highly soluble.


Sample Measured IDR

(mg/hr/cm2)

Predicted solubility,

Cs (mg/ml)

Crystalline drug

0.3 0.1

Amorphous drug

12.6 5.6

Difference 42x 43x

W.E. Hamlin, J.I. Northam and J.G. Wagner, Relationship between in vitro dissolution rates and solubilities of numerous compounds representative of various chemical species. J. Pharm. Sci. 54 (1965), pp. 1651–1653

L Yu, A Carlin, G Amidon and A Hussain. Feasibility studies of utilizing disk intrinsic dissolution rate to classify drugs. International Journal of Pharmaceutics, Volume 270, Issues 1-2, 11 February 2004, Pages 221-227

Formulation and process selection Practical benefits of amorphous drug


Tablets containing melt extruded drug substance:

• Perform significantly better than crystalline drug substance alone

• Perform similarly to capsules

• Contain more than 2x drug load of capsules

• Significant reduction in number of dosage units required

• Good in-vivo performance Capsule drug load = 10% w/w

Tablet drug load = 25% w/w

120100806040200

100

80

60

40

20

0

Time (minutes)

Dru

g di

ssol

ved

(%)

LMG capsuleDrug onlySolid dispersion tablet (100 mg)Solid dispersion tablet (25 mg)

Formulation and process selection Reasons for selecting amorphous by melt extrusion

Final process selection of melt extrusion was based on a range of factors, including:

• Superior product performance

• Only possibility of obtaining a stable formulation of the drug in the amorphous form

• Regulatory acceptability of components, including any solvents involved during manufacture (nano and lipid matrix formulations involved dissolution of drug in relatively large quantities of solvent during manufacture)

• Likelihood of successful commercialisation, including ability to scale-up, GMP manufacturing facilities and ease of developing a commercial supply chain


Process Development Extrusion process flow diagram

• API, 30% • Diluent, 69% • Glidant, 1%


Blending Melt extrusion Milling Blending Compression Coating

• Extrudate, 83% • Diluent, 15% • Lubricant, 1% • Glidant, 1%

• Coating solids • Purified water

Process Development Extrusion barrel setup

Ian Gabbott, Drug Product Development | 2014 10 Global Medicines Development | Pharmaceutical Development

Drivemotor

Powderfeeder

Vacuum

Extrudate

Zone1

Zone2

Zone3

Zone4

Zone5

Zone6

Zone7

Zone8 Die

Process Development Extrusion operating range determination

Ian Gabbott, Drug Product Development | 2014 11 Global Medicines Development | Pharmaceutical Development

Increasingcrystallinity

inextrudate

Operating window Temperature (T)Feed rate (FR)Screw speed (SS)

Unacceptablecrystallinecontent

Acceptablecrystallinecontent

Temperature (T)Feed rate (FR)Screw speed (SS)

Constant FR and SSConstant T and SSConstant T and FR

Process Development

• Significant number of tablet appearance defects prior to optimisation, including capping - hand sorting required. Primarily a result of formulation being dictated by performance and stability of amorphous drug substance.

• Tooling geometry found to be influential, was optimised and used for subsequent batch manufactures resulting in some improvement in appearance

• Post extrusion process (milling, blending, tabletting and coating) scaled up to intended commerical scale (80 kg)

• Coating process developed to achieve good tablet appearance, including trials involving debossed tablets

Overview of steps post extrusion


Process Development Effect of coating


Analytical Development Bioavailability

Mean bioaccessible fraction results determined by TIM-1 analysis

Good correlation between the level of crystalline drug and the resultant bioaccessible fraction


Analytical Development

• Use of hot stage microscopy in development

• Hot stage microscopy showed very low levels of residual crystalline drug substance during scale up of post extrusion (tabletting) processes

• A suitable method capable of detecting residual crystalline drug substance at bio-relevant levels was required

• Stability assessment also required - impact on shelf life and packaging requirements

Crystallinity


Compaction Study Factors and responses

Takes into account compression force deviation from target values and tablet weight variation as part of the model (ie, reflected in the estimate for the mean result value)


Stage Variables Type Milling Mill speed Factor Storage (humidity of environment) Moisture content (Loss on drying) Factor Compression Pre-compression force target Not used

Main compression force target Not used Actual pre-compression force applied Factor Actual main compression force applied Factor Tablet weight Factor Tablet ejection force Response Tablet breaking strength Response Tablet thickness Response

Compaction Study Tablet breaking strength


Design-Expert® SoftwareFactor Coding: ActualBreaking strength (kP)

CI Bands

X1 = B: MCP (MPa)X2 = D: Mill speed (rpm)

Actual FactorsA: PCP (MPa) = 105.90C: Weight (mg) = 213.72E: Relative humidity (%) = 8

D1 4500D2 9000D3 15000D4 18000

D: Mill speed (rpm)

87.36 166.24 245.12 324.00 402.88

B: MCP (MPa)

Brea

king

stre

ngth

(kP)

-5

0

5

10

15

20

25

Interaction

Model p-value: <0.0001 R-squared: 0.89



Design-Expert® SoftwareFactor Coding: ActualBreaking strength (kP)

CI Bands

X1 = B: MCP (MPa)X2 = D: Mill speed (rpm)

Actual FactorsA: PCP (MPa) = 105.90C: Weight (mg) = 213.72E: Relative humidity (%) = 58

D1 4500D2 9000D3 15000D4 18000

D: Mill speed (rpm)

87.36 166.24 245.12 324.00 402.88

B: MCP (MPa)

Brea

king

stre

ngth

(kP)

-5

0

5

10

15

20

25

Interaction



Breaking strength increases largely due to decrease in porosity of tablets facilitated by smaller particle size and/or increased moisture content for a given compression force


0.250.200.150.100.05

25

20

15

10

5

0

Tablet porosity (%)

Tabl

et b

reak

ing

stre

ngth

(kP

)

S 3.88455R-Sq 49.9%R-Sq(adj) 48.0%

Compaction Study Elastic recovery data

Elastic recovery of the tablet after compression is a function of compression force alone.

Therefore, lower compression forces are likely to be beneficial.


40353025201510

0

-2

-4

-6

-8

-10

-12

-14

Main compression force (kN)

Elas

tic

reco

very

(J)

45009000

1500018000

(rpm)Mill speed

Compaction Study Tablet ejection force


Design-Expert® SoftwareFactor Coding: ActualOriginal ScalePeak ejection force (kN)

X1 = E: Relative humidity (%)X2 = B: MCP (MPa)

Actual FactorsA: PCP (MPa) = 105.90C: Weight (mg) = 214.55D: Mill speed (rpm) = 4500

B- 87.36B+ 402.88

B: MCP (MPa)

8 23 43 58

E: Relative humidity (%)

Peak

eje

ctio

n fo

rce

(kN

)

0

0.05

0.1

0.15

0.2

Interaction


Compaction Study Conclusions


Stage Variables Conclusions Milling Mill speed (4500, 9000,

15000 and 18000 rpm) Increased mill speed: increased tablet breaking strength

Storage (humidity of environment – 8, 23, 43 and 58% RH)

Moisture content (Loss on drying)

Increased humidity/moisture content: increased tablet breaking strength, decreased tablet thickness, decreased tablet ejection force

Compression Tablet weight Increased tablet weight: increased tablet thickness

Pre-compression force target (0-15 kN)

No effect

Main compression force target (10-30 kN)

Increased main compression force: increased tablet breaking strength, decreased tablet thickness, increased tablet ejection force

Pilot scale study Factors and responses

Takes into account tablet weight variation as part of the model (ie, reflected in the estimate for the mean result value)


Stage Variables Values Type Milling Mill speed 14000, 16000, 18000 Factor Compression Pre-compression force target 0 Not used

Main compression force target

Low (approx 10 kN), Med (approx 20 kN), High (approx 30 kN)

Factor

Tablet weight Factor Tablet ejection force Response Tablet breaking strength Response Tablet thickness Response Tablet dissolution rate Response

Pilot scale study Tablet crushing strength results

Hardness increases with increasing force and mill speed.

Hardness should be maximised to reduce chance of breakages.


Mill speed (rpm)Main compression force (kN)

180001600014000HighMedLowHighMedLowHighMedLow

300

250

200

150

100

Har

dnes

s (N

)

Pilot scale study Tablet crushing strength results

Hardness increases with increasing force and mill speed.

Hardness should be maximised to reduce chance of breakages.


1800017000160001500014000

300

250

200

150

100

Mill speed (rpm)

Har

dnes

s (N

)

LowMedHigh

force (kN)compression

Main

Pilot scale study Pilot scale compression study results

Average tablet thickness decreases with increasing compression force. No significant effect of mill speed.


HighMedLow

6.6

6.5

6.4

6.3

6.2

6.1

Main compression force (kN)

Thic

knes

s (m

m)

140001600018000

(rpm)Mill speed

Pilot scale study Pilot scale compression study conclusions (so far)

In order to:

• Maximise tablet hardness and minimise tablet friability

• Minimise potential for elastic recovery

Mill speed should be maximised

Compression force should be reduced while still achieving good tablet tensile strength (>2 Mpa)


Pharmaceutical Melt Extrusion and Tabletting Overall conclusions

• Amorphous solid dispersion achieved by melt extrusion resulted in superior product performance when compared with other manufacturing processes.

• Tabletting of extruded material may not be straightforward (due to necessary use of components suited to extrusion), but experimental work can be performed in order to improve physical properties.

• Melt extrusion process route had additional benefits in terms of cost, flexibility, experience, relationships and suitability for commercial production.


Pharmaceutical Melt Extrusion and Tabletting References/acknowledgements

• W.E. Hamlin, J.I. Northam and J.G. Wagner, Relationship between in vitro dissolution rates and solubilities of numerous compounds representative of various chemical species. J. Pharm. Sci. 54 (1965), pp. 1651–1653

• L Yu, A Carlin, G Amidon and A Hussain. Feasibility studies of utilizing disk intrinsic dissolution rate to classify drugs. International Journal of Pharmaceutics, Volume 270, Issues 1-2, 11 February 2004, Pages 221-227



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