Mixing of powders. Wim Oostra

Transcription

1 Mixing of powders Wim Oostra

2 Introduction Concepts of mixtures Statistics Mechanisms of mixing Segregation Equipment Practice Scale - up References Content

3 Types of Mixtures

4 Types of Mixtures

5 Ordered Mixture

6 A good mixture?

7 Clusters

8 Simulation fraction of clusters [-] % 5% 10% cluster size [# spheres] Yi, Y.-B, C.-W. Wang and A. M. Sastry (2004), J. Electrochem. Soc., 151 (8), A1292-A1300, 2004.

9 NIR imaging millimeters millimeters

10 Measurements 1000 E2: Cluster distribution: Good vs Poor (concentration pixel > 8.1 w/w %) 100 Cluster frequentie 10 1 good poor Cluster size [mm]

11 Statistics, ideal case Two component system Particles differ only in color Binomial statistics

12 Statistics Average: y n = 1 y i n Standard deviation: σ = n 1 ( y i n 1 y) 2

13 Statistics, ideal case At complete segregation: 2 σ = p q Fully randomized for A particles: 2 σ = p A q

14 Statistics, real life Two component, multisized: Multi component with one key component: + = q a a p a a W f p W f q W p q ). ( ). (. 2 σ ( ) ( ) ( ) = r a a q a a p a a W f r W f q W f p p p W p σ

15 Mixing indices Lacey: M σ σ = 2 2 σ 0 σ r mixing occurred = mixing possible Poole, Taylor, Wall: σ M = σ r

16 Mixing indices sigma2 Lacey poole sigma [-] revs. [#] index [-]

17 Mechanisms of mixing Diffusion- redistribution of particles by random motion Convection - transfer from one location to another by external force Shear formation of slip planes

18 Diffusion

19 Diffusion

20 Diffusion

21 Convection

22 Convection

23 Convection

24 Convection

25 Shear dispersion

26 Shear dispersion

27 Shear dispersion

28 Segregation can be caused by: Difference in particle size Difference in density Difference in shape or a combination of these

29 Segregation Mechanisms Trajectory segregation

30 Segregation Mechanisms Percolation

31 Segregation Mechanisms Elutration

32 Segregation

33 Segregation

34 Segregation

35 Segregation

36 Types of mixers Tumbling mixers Convective mixers High shear mixers Fluidized mixers Hopper mixers Multi-purpose mixers

37 Tumbler mixers:

38 V-mixer

39 Bin blender

40 Double cone blender

41 Double cone blender

42 Drum

43 Drum

44 Drum

45 Ribbon blender

46 Nauta mixer

47 Nauta mixer

48 High shear mixer

49 Static mixer

50 Mixer selection

51 Ribbon blender

52 Rotocube

53 V-blender

54 Influence of size ratio

55 Mixing Strategies > 5-10% Direct blending 1-5% Preblending (non-geometric) <1% Preblending (Geometric) < 0.1% Solvent addition or Ordered mixing

56 Preblending (Nongeometric) Use KC 0.5 Example: 4% loading =20%, preblend 1 part in 4 parts and subsequently make final blend

57 Preblending (geometric) Mix equal parts of key component and other component ( Mixture 1) Mix equal parts of Mixture 1 and other component ( Mixture 2) Mix equal parts of Mixture 2 and..

58 Scale up of blenders Rotational velocity is key blending parameter Try to keep tip speed and momentum the same during scale-up As mass increases tip speed decreases

59 Scale up of blenders Small scale: Develop sampling methods, sample sizes and locations Evaluate blending times Production scale: Verify blending time and rotational speed

60 Sampling Powder should be in motion when sampled Better sample the whole stream for many short times than part of the stream for a long time Use revolving sample splitter for reduction

61 Sample splitters Method rsd [%] cone and quartering 6.81 scoop sampling 5.14 table sampling 2.09 Chute riffler 1.01 Spinning Riffler 0.125

62 Sample thieves Several different designs are available Accuracy varies strongly, not only between different designs but also in one design between different mixtures!

63 A Sample thief

64 Test the thief

65 Test the thief

66 Test the thief

67 Test the thief

68 Use the thief Consistent and standardized technique Angle of insertion Swivel Fast or slow Personnel training Glass vs plastic containers (static) Test entire sample Weigh sample containers before sample is added Rinse sample container with extra diluent Lab training

69 Blend Sampling Content [%] sample # P/T: 60%

70 Tablet sampling

71 Blend sampling

72 Blend sampling

73 Modern sampling (PAT), end point control On line NIR On line Raman Acoustic emission Effusivity.

74 PAT (1) 60 mg Gepirone Mixed 3-4 days after weighing HPMC Mixing time 15 minutes RSD HPLC 4.1% (after 3 wks) NIR spectra (immediately) 80 mg Gepirone Immediately mixed after weighing HPMC Mixing time 15 minutes RSD HPLC 1.3% (after 3 wks) NIR spectra (immediately) Gepirone NIR mengen 60 mg cp 0.06 NIR mengen Gepirone 80 mg gemiddelde absorptie [SNV 2nd-der] m60-01 m60-02 m60-03 m60-04 m60-05 m60-06 m60-07 m60-08 m60-09 m60-10 m60-11 m60-12 m60-13 m60-14 m60-15 m60-16 m60-17 m60-18 m60-19 m60-20 NIR spectrum [nm] Gemiddelde absorptie [snv 2nd-der] m80-01 m80-02 m80-03 m80-04 m m80-06 m80-07 m80-08 m80-09 m80-10 m80-11 m80-12 m80-13 m80-14 m m80-16 m80-17 m80-18 m80-19 m NIR spectrum

75 Risk management and PAT (2) 0.25 NIR Mengen Gepirone (spectrum; ) 60% som stdev [NIR NIR HPLC Parameter control (time) Quality-based Control (NIR value) 50% 40% 30% 20% 10% RSD Gepirone gehalte [HPLC] mengtijd [min] 0% Solution; change from parameter-based process control to quality-based control

76 A control strategy INPUTS Parameters Mixing time Mixing speed PSD Excipients PSD Active Moisture content excipients MIXING Blend uniformity RH Batch size Mixer type Critical

77 The desired control strategy INPUTS Parameters Mixing time Mixing speed NIR PSD Excipients PSD Active Moisture content excipients MIXING Blend uniformity RH Batch size Mixer type Not critical Critical for this unit operation Critical for other unit operation

78 A variety of mixers

79 Analyzer on V-blender

80 Result Mixing in Vrieco Nauta blender MBSD (AU) kg 35 kg 40 kg Time (Minutes)

81 Full scale F.04 A. Gerich, et.al. A generic in-line NIR method for blend uniformity control using a moving F-test.

82 Full scale data, batch 2, 29, 62 Sulub et.al.

83 Modern scale up Bin blender, two sizes 2 two component mixtures On line assesment of mixture quality through NIR probe Data used to determine effective mixing volume of mixers

84 Small scale

85 Large scale

86 Results Formulation Critical rotations Scale up coeff. Ditab Ditab Dihydrate Dihydrate

87 Modern approaches

88 References Powder Mixing, Brian Kaye, Chapman&Hall, 1997, ISBN Introduction to Particle Technology, Martin Rhodes, Wiley, 2000, ISBN Modelling of Powder Blending using On-line Near-Infrared Measurements, Drug. Dev. and Industrial Pharmacy, 27(7), (2001) Powder Mixing and Segregation, F.J. Muzzio, T. Shinbrot, Final Report IFPRI, May Sampling and characterisation of pharmaceutical powders and granular blends, F.J. Muzzio et. al., Int. J. Pharmaceutics, 250, 51-64, 2003 Particle size measurement, T. Allen, 5th ed. Chapman&Hall, 1994 A review on the continuous blending of powders, L. Pernenkil and CL.L. Cooney, Chemical Engineering Science, 61, , 2006 Blend uniformity end-point determination using near-infrared spectroscopy and multivariate calibration, Journal of Pharm. and Biomed. Analysis, In Press, Accepted Manuscript, Available online 18 February 2011 Yusuf Sulub, Michele Konigsberger, James Cheney