Pharmaceutical Melt Extrusion and Tabletting APS … · Pharmaceutical Melt Extrusion and...
Transcript of 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
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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
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Formulation and process selection Formulations containing crystalline drug
Nano-suspension
Formulation and manufacturing
• 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
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Formulation and process selection Formulations containing crystalline drug
Lipid matrix
Formulation and manufacturing
• 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
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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.
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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
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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
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Process Development Extrusion process flow diagram
• API, 30% • Diluent, 69% • Glidant, 1%
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Blending Melt extrusion Milling Blending Compression Coating
• Extrudate, 83% • Diluent, 15% • Lubricant, 1% • Glidant, 1%
• Coating solids • Purified water
Process Development Extrusion barrel setup
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Drivemotor
Powderfeeder
Vacuum
Extrudate
Zone1
Zone2
Zone3
Zone4
Zone5
Zone6
Zone7
Zone8 Die
Process Development Extrusion operating range determination
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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
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Process Development Effect of coating
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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
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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
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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)
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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
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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
Compaction Study Tablet breaking strength
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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
Model p-value: <0.0001 R-squared: 0.89
Compaction Study Tablet breaking strength
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
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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.
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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
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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
Model p-value: <0.0001 R-squared: 0.43
Compaction Study Conclusions
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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)
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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.
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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.
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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.
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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)
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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.
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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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