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Cosima Hirschberg, M.Sc.
University of Copenhagen25th January 2017Prague
Small scale formulation development
Who am I and where do I come from
25/01/2017 2
Cosima Hirschberg, M.Sc.Ph.D. student at the University of Copenhagen
Section head:Prof. Dr. Jukka Rantanen
2 Associate professors2 Assistant professors4 Post-Docs15 Ph.D. studentshttp://pharmacy.ku.dk/research/section-of-pharmaceutical-technology/
(04.01.2017)
https://en.wikipedia.org/wiki/The_Little_Mermaid_(statue)(04.01.2017)
Agenda
• Part I: Example from UCPH
• Part II: Research Example
1. Aim
2. Theoretical background
3. Results & Discussion
4. Conclusion
25/01/2017 3
Part I: Pharmaceutical Education at the University of Copenhagen
In 1892 The Royal Danish School of Pharmacy was founded
Today:
• B.Sc. in Pharmacy (Danish)
• M.Sc. in Pharmacy (Danish)
• M.Sc. in Pharmaceutical Sciences (English)
• M.Sc. in Medicinal Chemistry (English)
• Professional Master:
• Master of Medicines Regulatory Affairs (English)
• Industrial Drug Development (MIND)
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Dosage Form Formulation – Teaching
• Bachelor – mandatory course in dosage form manufacturing (Lægemiddelsfremstilling)
• Sterile dosage forms
• Semi-solid dosage forms
• Solid dosage forms:
capsules/ direct compaction/ wet & dry granulation / tableting
• Gamlen tableting press :
Small amounts of powder needed
Material saving
Force distance curve
Different calculations possible to evaluate the powder
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Comparison of the Compaction behaviour of 2 powders
• Mannitol and Corn Starch
• Double compression to analyse elastic behaviour
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(a) Packing(b) Compression(c) Elastic recovery(d) Plastic deformation
Changquan Calvin Sun, Journal of Adhesion Science and Technology 25 (2011) 483-499
GTP - punch
Tableting calculations
• Youngs modulus/ Elastic Modulus
Describes the deformation of an object to deform along an axis when opposing forces are applied along that axis.
• Heckel equation
Relation between the compaction pressure and the density of the powder bed*
Tablet porosity can either be measured in-die or on the ejected tablet
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* Simplified
Compression comparison/ 1st compression
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Work recovery during decompression
DecompressionCompression
Work of compaction
2. Compaction
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Elastic modulus
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Mannitol Corn starch
Corn starch shows more difference in tablet volume under 2nd compression -> more elastic behaviour
-> only very small amounts of powder needed
Part II: Research example – Aim
Visualization of the critical drug loading affecting the processability of a formulation for direct compression
• Use a small batch size
• Suitability for direct compaction
• Identifying the critical drug load
• Influence of different APIs
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Part II1. Aim2. Theoretical background3. Results & Discussion4. Conclusion
Hirschberg, Sun, Rantanen; JPBA 128 (2016) 462-468
Direct Compaction
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- Flowability of the formulation- Can we make a tablet ?
Part II1. Aim2. Theoretical background3. Results & Discussion4. Conclusion
Hirschberg Cosima, Master Thesis June 2015, University of Copenhagen
Powder flowability / Schulze ring shear tester
- Flowability
- Flowability under different consolidation stresses
- Friction on changing wall materials
- Compressibility
- Bulk density
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Sample preparation:Overfilling the shear cell and scraping off excess and creating a smooth surface
3,5 mL 30 mL 60 mL
Powder flowability / Schulze ring shear tester
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Pictures taken from “Powders and bulk solids: behavior, characterization, storage and flow” ; D.Schulze, 2008; Springer
𝑓𝑓𝑐 =𝜎1𝜎𝑐
(𝑎. 𝑢. )
Tableting/ Gamlen Tableting
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• Tableting : load cell 500 kg – CT6-500-022• Crushing: load cell 50 kg – CT6-050-012• Controllable parameters:
• Die speed• Load• Tablet height• Multiple compressions
• Tablet diameter: 6 mm• Calculation of the tensile strength:
𝜎 =2𝐹
106 ∗ 𝜋 ∗ 𝐷 ∗ 𝑇
F – breaking force (N)D – tablet diamter (m)T – tablet thickness (m)
Tablets
• Compressibility
• Ability of a powder to decrease in volume under pressure
• Compactability
• Ability of the powdered material to be compressed into a compact
• Tabletability 1
• Ability to form a tablet of adequate mechanical strength by powder compaction
1Sun; Journal of Adhesion Science and Technology 25 (2011) 483-499
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Used Formulation
Ingredient Use wt %
API * Active ingredient 0-80
Magnesium - Stearate Lubricant 0.5
Croscarmellose-Sodium Disintegrant 5
MCC PH102 : SuperTab 11SD **2:1
Filler Up to 100
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* Paracatamol 1&2 (refers to differnet size distribution)Ibuprofen-> High dose APIs
** Spray dried α - lactose monohydrate
Hirschberg, Sun, Rantanen; JPBA 128 (2016) 462-468
API Characterisation
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100 µm
PRC 1 PRC 2 IBU
Broken crystals Needle shaped crystals
Hirschberg, Sun, Rantanen; JPBA 128 (2016) 462-468
Part II1. Aim2. Theoretical background3. Results & Discussion4. Conclusion
API Characterisation
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d(0.1) (µm) d(0.5) (µm) d(0.9) (µm)
PRC 1 1.5 ± 0.0 5.5 ± 0.1 19.8 ± 1.0
PRC 2 1.8 ± 0.0 10.2 ± 0.2 72.6 ± 1.0
IBU 2.0 ± 0.0 12.0 ± 0.1 102.3 ± 4.2 n = 3
Hirschberg, Sun, Rantanen; JPBA 128 (2016) 462-468
Powder Flowability
• Flowability under low major principle stress:
• Chosen preshear : 800 Pa
• Average major principle stress: 1535 Pa
• Average bulk density: 0.506 g/cm³
-> Mimicking containers up to 20 L 1
• MCC PH102 defines the threshold for flowability ²
ffc = 5.1 ± 0.1
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1 Schulze (2008); Powders and bulk solids / ² Sun; PowTech 201 (2010) 106-108
Powder Flowability
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Hirschberg, Sun, Rantanen; JPBA 128 (2016) 462-468
API R² Critical concentration (%)
PRC 1 0.992 6.5 – 9.4
PRC 2 0.953 25.1 – 32.9
IBU 0.931 56.3 – 64.5
Tabletability
Threshold for tablet strength: 2 MPa 1
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API R² Critical concentration (%) – 160 MPa
PRC 1 0.991 23.6 – 26.7
PRC 2 0.998 26.6 – 29.8
IBU 0.968 42.7 – 48.7
1Sun, C.C., et al; J Pharm Sci, 2009. 98 (1), 239-47 / Hirschberg, Sun, Rantanen; JPBA 128 (2016) 462-468
Visualization of the processability
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Relative Flowability: measured flowability – threshold flowabilityRelative Tensile Strength: measured tensile strength – threshold tensile strength
Hirschberg Cosima, Master Thesis, June 2015
Visualization of the processability
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Hirschberg, Sun, Rantanen; JPBA 128 (2016) 462-468
Conclusion
• Small sample volumes were sufficient to determine the processability of a formulation and to determine the critical concentration that can be added to the formulation.
• Instruments using only small volumes of powder are advantageous in the development of solid dosage forms.
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Part II1. Aim2. Theoretical background3. Results & Discussion4. Conclusion
Acknowledgments
• Prof. Dr. Jukka Rantanen (University of Copenhagen)
• Assoc. Prof. Holger Grohganz (University of Copenhagen)
• Assoc. Prof. emeritus Jørn Sønnergaard (University of Copenhagen)
• Assoc. Prof. Changquan Calvin Sun (University of Minnesota)
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