small scale formulation development - technoprocur · small scale formulation development. ......

Cosima Hirschberg, M.Sc.

University of Copenhagen25th January 2017Prague

Small scale formulation development

Who am I and where do I come from

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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

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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 ?


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


API Characterisation

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100 µm

PRC 1 PRC 2 IBU

Broken crystals Needle shaped crystals



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


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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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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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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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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Thank you for your attention

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Contact details:

Cosima [email protected]

small scale formulation development - technoprocur · small scale formulation development. ......

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