Tuesday, February 3 rd, 2015 University of Eastern Finland, Tietoteknia building, lecture room 1035

Transcription

1 Mobile Course on QbD & PAT February 3-4, 2015, Kuopio, Finland co-organised by PROMIS Centre (UEF) and EUFEPS Day1: Tablet manufacturing Tuesday, February 3 rd, 2015 University of Eastern Finland, Tietoteknia building, lecture room 1035 Adjunct. Prof. Ossi Korhonen, UEF (ossi.korhonen@uef.fi) Jari Pajander, Novo Nordisk

2 Mobile Course on QbD & PAT February 3-4, 2015, Kuopio, Finland co-organised by PROMIS Centre (UEF) and EUFEPS

3 Mobile Course on QbD & PAT February 3-4, 2015, Kuopio, Finland co-organised by PROMIS Centre (UEF) and EUFEPS

4 Outline Introduction Quality attributes of tablets Particle deformation Particle bonding Compression cycle Parameters to monitor compression cycle Physical and pharmaceutical tablet analysis Future aspects of PAT in tableting

5 Advantages: Introduction Most common dosage form convenient Easy to produce in large scale Cheap production Stable (chemical, physical, microbiological) compared to liquid dosage forms Tablet monographs (13) in European Pharmacopoeia Uncoated tablets Coated tablets Gastro-resistant tablets Prolonged-release tablets Delayed-release tablets Pulsatile-release tablets Effervescent tablets Soluble tablets Dispersible tablets Orodispersible tablets Chewable tablets Tablets for use in the mouth Oral lyophilisates

6 Introduction cont. Disadvantages and challenges: Biopharmaceutical Poor bioavailability due to poor solubility or poor absorption Instability in gastrointestinal tract Local irritation Physical Homogeneity Segregation, especially in low dose Low compactability, especially in high dose Low mechanical strength: capping and lamination Adhesion or sticking to punches High friction

7 Tablets as the oral dosage form (Martin) Physical properties Polymorphism Crystallinity Melting point Particle size, shape, surface area Density Hygroscopicity Solubility as a function of ph Solubility in organic solvents Solubility in the presence of surfactants Dissolution Wettability Partition coefficient Chemical properties pka Solubility product of salt form Chemical stability in solution Chemical stability in solid state Photolytic stability Oxidative stability Incompatibility with formulation additives Complexation with formulation additives Mechanical properties Elasticity Plasticity Bonding Brittleness Viscoelasiticity Biological properties Membrane permeability ADME Metabolism

8 Quality attributes of tablets (According to Aulton s Pharmaceutics) The correct dose of the drug Weight, size, and appearance have to be consistent Drug should be released in a controlled and reproducible way Ingredients in tablet should be compatible with each other and human Sufficient mechanical strength Chemically, physically and microbiologically stable Packed in a safe manner

9 European Pharmacopoeia related tests for quality attributes of tablets The correct dose of the drug Uniformity of content of single-dose preparations Uniformity of dosage units Weight, size, and appearance have to be consistent Uniformity of mass of single-dose preparations Flowability Powder flow Gas pycnometric density of solids Specific surface area by gas adsorption Particle size analysis by laser light diffraction Particle-size distribution estimation by analytical sieving Bulk and tapped density of powders

10 European Pharmacopoeia related tests for quality attributes of tablets cont. Drug should be released in a controlled and reproducible way Disintegration of tablet and capsules Dissolution test for solid dosage forms Intrinsic dissolution Apparent dissolution Wettability of porous solids including powders Sufficient mechanical strength Friability of uncoated tablets Resistance to crushing of tablets

11 Requirements of powder for tableting Homogeneity! Equalities of ingredients: Density Particle size Particle shape Blending operation Good flowability Permanent particle deformation Particle-Particle bonding

12 Particle deformation under pressure Powder compressibility Powder propensity to reduce volume when subjected to a load Particle can reduce its volume by: Elastic deformation time-independent not permanent Plastic deformation time-independent permanent Fragmentation time-independent permanent Viscoelastic or viscous deformation time-dependent partly permanent

13 Particle deformation under pressure Elastic deformation time-independent Densification under load occurs due to small movement of molecules in the particle Densification depends only on load Densification or deformation is not permanent Volume Load

14 Particle deformation under pressure Plastic deformation time-independent Densification under load occurs due to the sliding of molecules along slip planes Densification depends only on load Densification or deformation is permanent Volume Load

15 Particle deformation under pressure Fragmentation time-independent Densification under load occurs due to the fracture of large particles to smaller particles Densification depends only on load Densification or deformation is permanent Volume Load

16 Particle deformation under pressure Viscoelastic or viscous deformation time-dependent Densification under load occurs due to the combination of elastic and plastic deformation Deformation is strain-rate sensitive Densification or deformation is partly permanent Volume Load

17 Particle deformation under pressure in reality All volume reduction mechanisms are simultaneously involved in tableting Relative magnitude of each mechanism defines the main behavior of volume reduction Highly material dependent Plastic deformation and fragmentation are desired timeindependent and permanent Elastic deformation is absolutely undesired

18 Particle bonding Powder compactability The compactability is the propensity of the powder to form a coherent tablet Tableting is fundamentally an interparticulate bonding process Rumpf classification of particle bonding Solid bridges Bonding by liquid Binder bridges Intermolecular and electrostatic forces Mechanical interlocking

19 Particle bonding In dry powder compaction intermolecular bonding and electrostatic forces and solid bridges are the main bonding mechanisms. Mechanical interlocking may play a role especially in plastic deformation Intermolecular and electrostatic forces (adsorption bonding) Weak and short range (10 50nm) interaction forces between molecules in the surface of particles Solid bridges (diffusion theory of bonding) It happens when two particles exchange surface molecules and fuse together. Requires increased molecular mobility which can be achieved by melting or temperature rise above Tg.

20 Compression cycle rotary tablet press = distance sensor = force sensor

21 Parameters to monitor compression cycle (Basics) Force Upper punch force Die wall force Lower punch force Ejection force

22 Parameters to monitor compression cycle (Basics) What effects on force? Particle rearrangement Particle-particle friction Particle-die wall friction Particle deformation Particle bonding Tablet ejection

23 Parameters to monitor compression cycle (Basics) Force as a function of time Shape of force-time curve depends deformation properties of material and the shape of punch head

24 Parameters to monitor compression cycle (Basics) Force as a function of time Elastic deformation Force Time

25 Parameters to monitor compression cycle (Basics) Force as a function of time Force Plastic deformation and fragmentation Time

26 Parameters to monitor compression cycle (Basics) Force as a function of time Viscoelastic deformation Force Time

27 Parameters to monitor compression cycle (Basics) Force as a function of time D min Force F max Displacement = A 1 A 2 Time

28 Parameters to monitor compression cycle (Basics) Force as a function of time = Ratio approaches 1 -> elastic deformation Ratio approaches 0 -> plastic deformation or fragmentation Small time difference indicates plastic deformation and fragmentation Large time difference indicates viscoelastic deformation NOTE! Sensitive for tableting machine, compression force and speed, especially in viscoelastic deformation

29 Parameters to monitor compression cycle (Basics) Force as a function of time (single-punch) Force Upper punch force Lower punch force Die wall force Time

30 Parameters to monitor compression cycle (Basics) Force as a function of time (single-punch) Friction: Particle particle and particle die wall friction is characterized as a ration between lower and upper punch forces. Ratio close to 1 is the indication of well lubricated powder.

31 Parameters to monitor compression cycle (Basics) Force as a function of displacement Compression profile Force Elastic deformation Displacement

32 Parameters to monitor compression cycle (Basics) Force as a function of displacement Plastic deformation and fragmentation Compression profile Force Force

33 Parameters to monitor compression cycle (Basics) Force as a function of displacement Viscoelastic deformation Compression profile Force Displacement

34 Parameters to monitor compression cycle (Basics) Force as a function of displacement Viscoelastic deformation Compression profile Force Displacement

35 Parameters to monitor compression cycle (Basics) Force as a function of displacement Force Upper punch compaction work Displacement

36 Parameters to monitor compression cycle (Basics) Force as a function of displacement Force W u p W lo Displacement

37 Parameters to monitor compression cycle (Basics) Force as a function of displacement Force Expansion work Displacement

38 Parameters to monitor compression cycle (Basics) Force as a function of displacement Net work = W up W fri W exp, work done for permanent deformation and bond formation Force W net Displacement

39 Parameters to monitor compression cycle (Basics) Volume/porosity as a function of compression pressure Heckel equation 1 ) = 1 Decompression phase Compression phase Pressure (MPa)

40 Parameters to monitor compression cycle (Basics) Volume/porosity as a function of compression pressure Heckel equation 1 = Slope = k Intercept = A 1 1 Pressure (MPa)

41 Parameters to monitor compression cycle (Basics) Volume/porosity as a function of compression pressure Heckel equation 1 = 1 Pressure (MPa)

42 Parameters to monitor compression cycle (Basics) Volume/porosity as a function of compression pressure Heckel equation Plastic and viscoelastic 1 = Fragmentatio n 1 1 large = is small = is large Pressure (MPa) Pressure (MPa)

43 Parameters to monitor compression cycle (Basics) Volume/porosity as a function of compression pressure Yield pressure and compression speed (punch velocity) %) = 100% 1 Plastic and viscoelastic 1 Fragmentation Pressure (MPa) Pressure (MPa)

44 Parameters to monitor compression cycle (Basics) Volume/porosity as a function of compression pressure Physical meaning of Heckel parameters: P Y describes the pressure where the deformation starts How much pressure is needed for the deformation D 0 bulk density D A tap density D B describes the amount of densification by the particle rearrangement and fragmentation before the deformation 1 Low SRS% for fragmentation and plastic (time independent) Large SRS% for viscoelastic deformation (time dependent) Pressure (MPa)

45 Parameters to monitor compression cycle (Basics) Volume/porosity as a function of compression pressure Decompression phase describes the elastic recovery of tablet 1 Decompression phase Compression phase Pressure (MPa)

46 Parameters to monitor compression cycle (Basics) Volume/porosity as a function of compression pressure Over compression : elastic deformation of tablet at high compression pressure 1 Tablets strength Pressure (MPa) Pressure (MPa)

47 Parameters to monitor compression cycle (Basics) Volume/porosity as a function of compression pressure If you do not have a displacement sensor in your tableting machine, you can measure Out of die yield pressure in stead of In-die. Make a series of tablets with increasing compression pressures. Measure tablet dimensions and calculate relative densities. 1 Pressure (MPa)

48 Parameters to monitor compression cycle (Basics) Volume/porosity as a function of compression pressure Challenges with Heckel equation Extremely sensitive for true density and mass of your powder/tablet. Displacement measurement: take into account punch and tableting machine deformation.

49 Physical and pharmaceutical tablet analysis Basics of tablet analysis according to Pharmacopoeia Drug should be released in a controlled and reproducible way Disintegration of tablet and capsules Dissolution test for solid dosage forms Intrinsic dissolution Apparent dissolution Wettability of porous solids including powders Sufficient mechanical strength Friability of uncoated tablets Resistance to crushing of tablets

50 Physical and pharmaceutical tablet analysis Advanced tablet analysis Transmission terahertz pulse delay measurements Fast (couple of millisec), possible to measure every tablet Need to know beforehand: intrinsic refractive index and density of material Tablet properties which can be derived: Tablet porosity (error less than 1%) Tablet weight (within couple of mg, but some offset) Detection of porosity of pharmaceutical compacts by terahertz radiation transmission and light reflection measurement techniques Prince Bawuah a,*, Alessandra Pierotic Mendia a, Pertti Silfsten a, Pertti Pääkkönen a,tuomas Ervasti b, Jarkko Ketolainen b, J. Axel Zeitler c, Kai-Erik Peiponen a International Journal of Pharmaceutics 465 (2014) Non-contact weight measurement of flat-faced pharmaceutical tablets using terahertz transmission pulse delay measurements Prince Bawuah a,b,*, Pertti Silfsten a, Tuomas Ervasti c, Jarkko Ketolainen c, J. Axel Zeitler b, Kai-Erik Peiponen a International Journal of Pharmaceutics 476 (2014) 16 22

51 Physical and pharmaceutical tablet analysis Advanced tablet analysis NIR and Raman spectroscopy Advantages Fast Quite sensitive Fairly easy to implement Disadvantages: Requires careful calibration models (multivariate) Surface measurement -> surface homogeneity vs. bulk homogenity Near infrared and Raman spectroscopy for the in-process monitoring of pharmaceutical production processes T. De Beera,, A. Burggraevea, M. Fonteynea, L. Saerensa, J.P. Remonb, C. Vervaetb International Journal of Pharmaceutics 417 (2011) 32 47

52 Physical and pharmaceutical tablet analysis Advanced tablet analysis NIR and Raman spectroscopy Sensors in feed frame PAT for tableting: Inline monitoring of API and excipients via NIR spectroscopy Patrick R. Wahl a, Georg Fruhmann a, Stephan Sacher a, Gerhard Straka b, Sebastian Sowinski c, Johannes G. Khinast a,d, European Journal of Pharmaceutics and Biopharmaceutics 87 (2014)

53 Physical and pharmaceutical tablet analysis Advanced tablet analysis NIR and Raman spectroscopy Tablet measurement In-line monitoring of the drug content of powder mixtures and tablets by near-infrared spectroscopy during the continuous direct compression tableting process Kristiina Järvinen a,, Wolfgang Hoehe b, Maiju Järvinen a, Sami Poutiainen a, Mikko Juuti c, Sven Borchert b European Journal of Pharmaceutical Sciences 48 (2013)

54 Thank you