THE INDIAN PHARMACIST

Scientific Section

Volume: XIX, No. 05 SEPTEMBER-OCTOBER 2021

Correspondence and manuscripts should be addressed to

The Editor, Scientific Section, ‘The Indian Pharmacist’,
F-8, Hauz Khas Enclave, New Delhi-110 016, India.

Case Study
THE EFFICIENCY OF POWDER BLEND
HOMOGENEITY IN LOW-DOSE DPI
PREPARATIONS USING THE
ALPHIE 3D TUMBLER MIXER
Metin Karabulut, Cigdem Acar and Jigar Talati

A. Introduction: speed (rpm), mixing time (min) and the mixing volume
(L).
Inhalation formulations are a way of treating the
symptoms of respiratory diseases[1]. Dry Powder Inhalers
(DPIs) for oral administration are prepared by mixing the
micronised drug in a granulated or sieved powder diluent
or carrier suitable for application to the lungs.
In this study, sieved and milled grades of lactose
monohydrate were used to create formulations
containing Formoterol Fumarate Dihydrate (FFD),
using the geometric zero-shear mixing technique.
The objective of the study was to evaluate the mixing
efficiency of the equipment, Alphie 3D mixer, and the
dependency of the low-dose DPI formulation blend
homogeneity to applied process parameters, mixing Photo 1: Alphie 3D Mixer
METIN KARABULUT and CIGDEM ACAR, Research & Development Center, World Medicine İlaç San. ve TİC.
A.Ş., İstanbul, Turkey. JIGAR TALATI, Founder Director & Principal Designer, M/s Hexagon Product Development
Pvt. Ltd., Por-391 243, India.
Address correspondence to JIGAR TALATI, Founder Director & Principal Designer, M/s Hexagon Product
Development Pvt. Ltd., Por-391 243, India (Email: info@alphiemixer.com, URL: www.alphiemixer.com).

THE INDIAN PHARMACIST | Vol. XIX | No. 04 | JULY-AUGUST 2021 1

n Efficiency of Powder Blend Homogeneity Figure2

Table 1: Process Parameters Factorial Design for Regression for FFD Homogeneity, mcg/g vs Mixing time, min
Formoterol Fumarate Dihydrate Blend Y: FFD Homogeneity, mcg/g
Summary Report

X: Mixing time, min

3
Fitted Line Plot for Linear Model
Factors: Is there a relationship between Y and X? Y = 425,5 + 0,0928 X

0 0,05 0,1 > 0,5

Runs: 60

FFD Homogeneity, mcg/g

Yes No 460

P = 0,683
Blocks: None Centre pts (total): 0 The relationship between FFD Homogeneity, mcg/g and 440
Mixing time, min is not statistically significant (p >
0,05).
420

Display Order: Run Order % of variation accounted for by model

400
0% 100%
5 10 15 20 25
Display Units: Uncoded Mixing time, min

R-sq (adj) = 0,00%

Comments
0,00% of the variation in FFD Homogeneity, mcg/g can
be accounted for by the regression model. The fitted equation for the linear model that describes the
relationship between Y and X is:

Factors and their Uncoded Levels Y = 425,5 + 0,0928 X

If the model fits the data well, this equation can be used
Correlation between Y and X to predict FFD Homogeneity, mcg/g for a value of Mixing
Negative No correlation Positive time, min, or find the settings for Mixing time, min that
correspond to a desired value or range of values for FFD
-1 0 1
Homogeneity, mcg/g.
Factor Name Low High
0,05 A statistically significant relationship does not imply that X
causes Y.
A Mixing speed, rpm 10 30 The correlation between FFD Homogeneity, mcg/g and
Mixing time, min is not statistically significant (p >
0,05).
B Mixing time, min 5 25
Figure 2: Minitab Regression for FFD Homogeneity, mcg/g versus
C Mixing volume, L 20 120
Mixing time, min
The study furtherly able to be evaluated on particle C. Results and Discussion:
interactions between the active sites on carriers in terms
of adhesive and cohesive forces and their relation with Table 1 shows the independent variables and their
zero-shear mixing design. associated responses for the low-dose formulation. The
optimization graphs (Figures 1, 2 & 3), indicated the
B. Methods: relationship between homogeneity amounts and related
variables were not statistically significant, in terms of
The blend homogeneity of low-dose DPI formulation, mixing speed (rpm), mixing time (min) and the mixing
active concentration of 0.048% (w/w), were evaluated volume (L) with p-values of 0.319, 0.683 and 0.323,
using the HPLC system (Agilent, Empower). The respectively (p ˃ 0.05).
amount of FFD were determined on 12 different sites of
the total powder blend. Each set had 12 sampling points ● Regression for FFD homogeneity, mcg/g versus
for each factorial design of total 60 runs (Minitab LLC. mixing speed, rpm; mixing time, min; mixing volume, L
Inc.) (Table 1). These were made by blending FFD with (20L, 50L & 120L).
milled grade lactose Respitose ML001 (DFE Pharma) Table 1 defines the factorial design which includes
carrier particles. independent process parameters and their possible
The particle morphology of the powder blend was also accepted range. Using three-factorial design method,
evaluated using Scanning Electron Microscope (SEM, experiments were performed to investigate the possible
magnification
Figure 1 20,000X). effect / or interaction of mixing speed (rpm), mixing
Figure3

Regression for FFD Homogeneity, mcg/g vs Mixing speed, rpm Regression for FFD Homogeneity, mcg/g vs Mixing volume, L
Summary Report Summary Report
Y: FFD Homogeneity, mcg/g Y: FFD Homogeneity, mcg/g
X: Mixing speed, rpm X: Mixing volume, L
Fitted Line Plot for Linear Model Fitted Line Plot for Linear Model
Is there a relationship between Y and X? Y = 430,8 - 0,2174 X Is there a relationship between Y and X? Y = 423,8 + 0,04108 X

0 0,05 0,1 > 0,5 0 0,05 0,1 > 0,5

FFD Homogeneity, mcg/g
FFD Homogeneity, mcg/g

Yes No 460 Yes No 460

P = 0,319 P = 0,323
The relationship between FFD Homogeneity, mcg/g and 440 The relationship between FFD Homogeneity, mcg/g and 440
Mixing speed, rpm is not statistically significant (p > Mixing volume, L is not statistically significant (p >
0,05). 0,05).
420 420

% of variation accounted for by model % of variation accounted for by model

400 400
0% 100% 0% 100%
10 15 20 25 30 30 60 90 120
Mixing speed, rpm Mixing volume, L

R-sq (adj) = 0,02% R-sq (adj) = 0,00%

Comments Comments
0,02% of the variation in FFD Homogeneity, mcg/g can 0,00% of the variation in FFD Homogeneity, mcg/g can
be accounted for by the regression model. The fitted equation for the linear model that describes the be accounted for by the regression model. The fitted equation for the linear model that describes the
relationship between Y and X is: relationship between Y and X is:
Y = 430,8 - 0,2174 X Y = 423,8 + 0,04108 X
If the model fits the data well, this equation can be used If the model fits the data well, this equation can be used
Correlation between Y and X to predict FFD Homogeneity, mcg/g for a value of Mixing Correlation between Y and X to predict FFD Homogeneity, mcg/g for a value of Mixing
Negative No correlation Positive speed, rpm, or find the settings for Mixing speed, rpm that Negative No correlation Positive volume, L, or find the settings for Mixing volume, L that
correspond to a desired value or range of values for FFD correspond to a desired value or range of values for FFD
-1 0 1 -1 0 1
Homogeneity, mcg/g. Homogeneity, mcg/g.

-0,13 A statistically significant relationship does not imply that X 0,13 A statistically significant relationship does not imply that X
The correlation between FFD Homogeneity, mcg/g and causes Y. The correlation between FFD Homogeneity, mcg/g and causes Y.
Mixing speed, rpm is not statistically significant (p > Mixing volume, L is not statistically significant (p >
0,05). 0,05).

Figure 1: Minitab Regression for FFD Homogeneity, mcg/g versus Figure 3: Minitab Regression for FFD Homogeneity, mcg/g versus
Mixing speed, rpm Mixing volume, L

2 THE INDIAN PHARMACIST | Vol. XIX | No. 04 | JULY-AUGUST 2021


Figure 4: SEM micrographs at 20,000X and 10,000X magnification (scale bar indicates 1 µm). Zero-shear blend particles (2a), and
shear applied blend particles (2b).
time (min) and mixing volume (L) on powder blend
homogeneity (mcg/g).
According to Figure 1, it can be resulted that the
relationship between FFD blend homogeneity and the
mixing speed, rpm, is not statistically significant at 'p'
value of 0.319 (p > 0.05). The trend of FFD homogeneity
(mcg/g) results is nearly constant where an increase in
mixing speed, 10 to 30 rpm, do not have a significant
effect on obtained blend homogeneity between the values
of 428.62 mcg/g to 424.27 mcg/g.
Figure 2 shows that the relationship between FFD
blend homogeneity and the mixing time, min, is not
statistically significant at 'p' value of 0.683 (p > 0.05).
The graphical trend of FFD homogeneity (mcg/g) line is
nearly constant where the increase in the mixing time, 5 to
25 minutes, does not have a significant effect on obtained
blend homogeneity between the values of 425.96 mcg/g
to 427.82 mcg/g.
The achievement of decreasing mixing time is a very
cost-effective parameter during production as well.
Figure 3 shows that the relationship between FFD
blend homogeneity and the Mixing volume, L, is not
statistically significant at 'p' value of 0.323 (p > 0.05).
The graphical trend of FFD homogeneity (mcg/g) line is
nearly constant where the increase in the mixing volume,
20 to 120L, does not have a significant effect on obtained
blend homogeneity between the values of 424.62 mcg/g
to 428.73 mcg/g.
The Alphie 3-D Mixer showed that the container
volume can be effectively used for different batch sizes
where obtained homogeneity results stay nearly constant
with precise and robust blend results. The minimum
workable volume were selected as 13.785% for each
container size, 20L, 50L and 120L. The peripheral speed
settled as a constant value of 0.416 m/s for each container
trial.
Figure 4 shows the morphology of zero-shear mixed
blend, API-containing powder blend (2a) and sieving-
shear applied API-containing lactose mixture (2b). The
zero-shear blend morphology have a uniform appearance
in contrast to the shear applied lactose mixture which
THE INDIAN PHARMACIST | Vol. XIX | No. 04 | JULY-AUGUST 2021
Efficiency of Powder Blend Homogeneity n
appears as more cracks on agglomerates.
D. Conclusion:
If considered the low-dose DPI product, the mixing
efficiency can be described as an independent parameter
from variables in terms of mixing speed (rpm), mixing
time (min) and the mixing volume (L) which indicates
that the critical factor is an equipment design. This
concluded from the zero-shear mixing on active agent
particles allows them attached mechanically easily on
carrier surface without cracks, and enables this structure
aerodynamically suitable with the efficient and effective
therapeutic DPI systems in particular.
Alphie 3D mixers are ideal for such blending as they
operate on the kinematic inversion principle having
minimal centrifugal force.
E. Acknowledgements:
The work was supported by World Medicine İlaç San.
ve San. A.Ş. The authors thank the founder & chairman
of the company, Rovshan Tagiyev, and the CFO, Sohrab
Mammadov.
F. Abbreviations:
API = Active Pharmaceutical Ingredient. DPI = Dry
Powder Inhaler. FFD = Formoterol Fumarate Dihydrate.
HPLC = High Performance Liquid Chromatography.
RPM = Revolutions Per Minute. SEM = Scanning
Electron Microscope.
G. References:
1. Cordula Weiss, Peter McLoughlin, Helen Cathcart:
Characterisation of dry powder inhaler formulations
using atomic force microscopy, International Journal of
Pharmaceutics, 2015, 494: 393-407. 
3