This document provides an overview of blending as a unit operation in pharmaceutical manufacturing. It discusses the mechanisms of mixing, including convection, diffusion, and shear. Scale-up considerations are outlined, along with ways to minimize segregation. Methods for assessing powder blend uniformity include sampling and assay testing, with limitations of traditional sampling thieves discussed. Overall, blending is a critical step for ensuring uniform distribution of active and inactive ingredients in pharmaceutical products.

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Blending - A unit operation
Instructed by : Dr. B. Rohera
Presented by : Niketkumar B.Patel
X01801641

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Outline :
 Introduction
 Mechanism of mixing
 Scale up in mixing
 Segregation
 Powder blend uniformity
 Conventional approaches
 Thermal effusivity measurement
 NIR spectroscopy as a PAT initiative
 Laser induced fluorescence technique
 Summary

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Introduction :
 Blending/mixing is the most common operation that can be
observed in many industries like food, glass, paints, ceramic,
fertilizers and pharmaceutical industry.
 Blending indicates much smoother and inseparable mixing of the
particles but both terms can be used interchangeably.
 Mixing is “putting together one or more substances into one mass
and ensuring their complete diffusion among each another.”
 With respect to pharmaceutical industry mixing would be
the “production of a blend whose sample reflects exactly, or at least
by pre-defined accuracy, the ratio of the added base materials. “

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Mixing :
Active substances + excipients
↓
Mixing
↓
Granulation
↓
Compression
↓
Packaging
Main goal of blending processes is
tablet production which requires
identical ingredients and
homogenous distribution of the
active pharmaceutical ingredient
(API) as well as additives.
Problems in blending
 inhomogeneity in material blends
 deblending due to exceeded
blending times
 increased time and cost
consumption due to exceeded
blending timesPharmaceutical industry –
solid blend of agent (API) and
several additives (up to 10)
are mixed together.

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Mechanisms of mixing :
Convection :
 Involves transfer of groups of particles as a mass (mainly parallel to flow)
 Convective mixing occurs when circulation patterns are set up in a powder
mix.
 Motion imparted by impeller as in Ribbon Blender.
Diffusion :
 Redistribution of particles by random motion
 Vertical or axial motion as seen in rotational blenders.
Shear :
 It involves movement of particles within a group of relatively slow moving
particles.
 There is formation of slip planes in the mixture.
 Motion imparted by high shear mixers.

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Scale up :
 It involves scaling up the quantities of the materials after achieving process
parameters such as content uniformity, particle size and distribution, surface
area and potency at a small scale.
 Various parameters are to be determined at a small scale like mixing time,
speed of mixing, volume of charged powder mix and energy imparted to
mix.
 During scale-up, it is essential to evaluate every possible effect that
modifications to the mixer size may encounter.
 Critical parameters for the given materials which would affect the process
parameters most can be determined at the pilot scale only.
 Drug deficiency has also been found to be a problem with scale-up due to
the adsorption of drug to the wall of the mixer, which did not happen on the
pilot scale.

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Several points to be followed during scale up
process :
 Changes in the scale during scaling up should not change the dominant
mixing mechanism (eg convective to dispersive).
 For free flowing materials, the number of revolution is more important rather
than rotation rate.
 For the cohesive materials, mixing depends on shear rates so rotational rate
is more important.
 Adding asymmetry to the mixer; either via design or via introduction of the
baffles can largely affect the mixing process
 In the case of upgrading the equipment or selection of new mixer- it leaves
behind all the data of the materials for the old mixer invaluable.

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Segregation :
 Segregation is a main problem to be encountered with during mixing
process; also known as demixing.
 Segregation refers to the separation of the coarse from fine material during
the flow of a powder or the vibration of a bed of powder.
Segregation is a function of
 The powder itself physical and chemical properties size density charge
cohesion
 Forces induced on the particles…air flow vibration gravity
 Flow sequence…due to equipment
 Overmixing- mixing after achievement of homogeneity of powder blend may
also cause segregation.

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Continue..
There is three types of segregation :
Size segregation
Density segregation
Trajectory segregation
Several approaches to minimize segregation :
 Ordered mixing can minimize segregation.
 Granulation can be also carried out to prevent segregation.
 Changes in particulate characteristics of drug and excipients may eliminate
particle size differences or improve adhesion between a coarse diluent and
fine particle drug.
 Avoiding sloping surfaces in machinery will also help reduce segregation.
 BINSERT is the instrument which is used to minimize segregation.
Segregation is the property of material and equipment so it can be minimized;
not prevented.

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Powder blend uniformity :
 Powder Blend Uniformity - refers to active ingredient distribution or
homogeneity in the “final” blend or mix.
 Powder Blend is encapsulated, tabletted, or filled into single or multiple
dosage units so in this case powder blend uniformity is important in deciding
quality of end product.
 “Adequacy of Mixing” - satisfactory blending step to assure uniformity and
homogeneity is a term used by the US Food and Drug Administration (FDA)
for powder blend uniformity.
Product non uniformity occurs due to
 Due to blend nonuniformity
 Due to segregation
Blend non uniformity occurs due to
 Due to poor blending
 Due to sampling errors

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 The content uniformity of the tablets is an important quality measure of the
final product.
 As the content uniformity is closely related to the uniformity of the blend, it
is important to monitor blend uniformity.
 Inhomogeneities of a blend can either be due to insufficient mixing or to
deblending under transportation or storage of the blend.
 Blend uniformity is a function of both the formulation and the mixing action.
 Overmixing is also a reason for segregation which causes a blend
uniformity.

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Blending non uniformity:
Insufficient blending and overblending both cause severe problems as
discussed below.
 Insufficient blending results in the lack of content uniformity can lead to
product recall by the FDA for subpotency or super-potency reasons.
 Recalls for sub-potency represent the top reason for
 drug recalls in current days
If blending is excessive,
 then the particles will segregate (demix or deblend) on the basisof particle
size and mass which again lead to problems in content uniformity.
 In addition, temperature increases that occur during blending can damage
some of the sensitive components and eliminate the potential for
continued blending to return the mixture to a homogenous state.
So determination of blending uniformity and blending end point is very
important.

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FDA perspective :
According to CGMP CFR TITLE 21 PART 211 mainly 211.110 for
sampling and testing of in process material and end products of
subparts f state the proposed three criteria by FDA
 Assay one sample per location , n ≥ 10
 RSD for all individual results ≤ 5 %
 All individual RESULTS within 10.0% of mean
 NIR spectroscopy is getting attention as ”real” time process control
which also facilitates PAT initiation.
So sampling is the primary requirement for the assay.

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Sampling for an assay :
 The most commonly used method fro deciding blend uniformity is withdrawing
samples from the blend and carrying out assay using HPLC or UV.
 In practice blend uniformity is assessed by collecting a number of samples from
the blend, each sample being of the size of 1-3 times the corresponding tablets;
which is a requirement.
 The sampling locations must be carefully chosen to provide a representative
cross-section of the granulation. The resulting samples are then assayed using
the same methods used to analyze the finished product.
 Content uniformity is established if the drug content of the samples conform to a
predetermined criterion.
 Currently sampling is done with sampling thief probe that is inserted into the
powder mixture to withdraw the samples.
 Thief probes make sampling possible from the bottom and middle portions of
the mix also.

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Groove thief End cup sampler
This device consist of an outer hollow
sleeve with an opening running the length of the
pipe (66 in.) which surrounds a rotating inner
pipe. This inner pipe is solid except for a
sampling cavity running the length of the pipe.
This sampler consists of a pair of thin
rods, one has a cup mounted at the end, the
other is attached to a rotating cap aligned with
the top of the cup.
A major drawback of this sampler is that only a
single sample can be acquired at a time.

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Problems with sampling thieves:
 Sampling with a thief probe is not a good method to carry on blending
homogeneity on it.
 This method always keep a question in front “Is this poor blending or
inaccurate sampling ??” responsible for blending in homogeneity.
 The whole validated blending process is carried out on the basis of
“nonvalidated” sampling method.
There is two golden rules for sampling :
 Sample should be taken from a moving stream of powder, and
 Sample the whole stream for equal periods of time, rather than from part of
the stream for all of the time
None of them can be fulfilled when we are using a thief probe for sampling.

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 Thief probes often exhibit large uncertainty and error due to the disruption of
the powder bed by the probe while inserting it in a powder blend for
sampling.
 Another main concern is the uneven flow of different powder species into
the probe during sampling.
 Several times it is hard to push thief probe in the mix and application of
force may break the particles.
 While taking the thief probe out of the mix after sampling, surface material
may contaminate the sample.
 Not even a standard probe or specifications for that is available.
 So sampling with thief probe is not trustworthy.

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Stream sampling
 Stream sampling is also an alternative to the
use of sample thieves. This report describes
the implementation of stream sampling by
capturing the blend in stainless steel cups as it
flowed from the bottom of the blender.

This type of sampling follow the two golden
rules of sampling.
 More number of samples can be taken
compare to sampling thief because there is no
possibility of particle breakage during sampling.
 Stream sampling is not able to target locations
that are suspected of providing poor blending.
 The goal of stream sampling is to obtain
representative samples and not to target
specific locations, which it actually does.
Schematic representation of
stream sampling.
So none of the methods looks efficient for carrying out an assay.

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Carrying out an assay:
 Samples collected as indicated above are sent to UV spectroscopy
and High pressure liquid chromatography for assay.
 Assay for the active ingredients are carried out and all data is collected and
various statistical approaches are used for the determining powder blend
homogeneity.
 Sometimes, to avoid repeataion of the sampling due to above discussed
disadvantages three or four assays are carried out with the help of one
sample.
 They give off line measurement of the blend uniformity because sampling is
the prerequisite to carry out the assay.
 Most widely and well accepted current method for determination of blending
uniformity is HPLC due to Precision, Reproducibility, Sensitivity and Solution
Stability - Up to 24 hr.

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Assessment of blend uniformity :
Round
represents the
results from the
left side samples
Square
represents the
result from the
right side
samples
Triangle
represents the
average potency
So as the potency of left side and right side samples approaches average
potency ; blend uniformity is meant to be developed

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Problems with the assay methods:
 The limitations of these tests lie in their inherent analysis time as
well as the necessity of removing samples from the blender.
 Errors occurs during the sampling or limitation of conventional
sampling method limits the accuracy of this method
 In this sense, blend homogeneity obviously addresses only the
distribution, i.e. the content uniformity of the active drug substance
while assuming that the excipients are also evenly distributed.
 The role of the excipients,which not only improves dosage form
compliance, but also affects the technological and
biopharmaceutical performance of the formulation, is simply
neglected.

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Thermal effusivity measurment :
 Simple and advanced method which gives an idea about blend
homogeneity and blending end poit.
 It is nondestructive method of analysis.
 E f f u s i v i t y = k ρ c p
 the thermal conductivity (k), heat capacity (cp), and density ( p ) of the
material.
So, powders would have different effusivity readings depending on their
ability to transfer heat through and between their particles.
And the resultant powder blend has its unique thermal effusivity which all
the powders ultimately going to achieve at the point of blending
homogenity.

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Carrying out a determination :
 Eight individual powder components of a commercially available formulation
were evaluated for their effusivity measurement
 Each has a different effusivity…measured…range for the experiement is
determined
 Triplicate results have taken ….low standard deviation among results should
be obtaied
Figure : component effusivity; range of 180 to 600 is obtained.

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Continue..
 Figure 3 shows the results of testing the second set of samples
extracted at various times from a commercial blender. As shown for
the previously described method, each point on the graph represents
the result of triplicate tests conducted on one aliquot from the vial
trend in the average results is to increase and then level off.
 The increase is suspected to result from improved packing, which
removes air from the volume of material tested

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Continue…
Figure indicates the change in effusivity in the first 15 min of blending and shows the six
individual results rather than the average.
 As the blending increase ….concentration of individual components
reduces….whereas blend concentration increase till the homogeniety
achieved.
 The first sample,drawn at 2 min, had a large scatter in the results
because of the nonuniformity that existed at the beginning. As the
blending time progressed toward 15 min, the repeatability improved as
an indicator of the uniformity.

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Continue…
 Relative standard deviation of effusivity of six samples are
taken which approaches the minimum value which is
achieved at the blending end point.
+
 Relative standard deviation is minimum at end point for this
off line manner measurment
Figure indicates RSD as determination of blending endpoint

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Advantages
 Non-destructive process - does not alter excipients or other ingredients
 Eliminates thieving - does not compromise containment
 Retrofittable - can be incorporated on existing blending equipment
 Easy to clean and maintain
 Accurate results - strong correlation with HPLC and other methods
 Cost savings - reduces operating costs and lost revenue due to discarded
batches
 Reduced liability risk
 Improved batch traceability
 EPS sensor package is the available instrument on this technology.
 But this technique gives offline measurement which lacks it in PAT initiation
compare to Near Infra red spectroscopy.

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Near infra red spectoscopy :
 Near Infrared Spectroscopy (NIRS) is a versatile analytical technique when
analyzing solids powders.
 It is based on dipole moment changes and molecular vibration altransitions
of molecules.
 The absorptions in this region are due to overtones and combination bands
of the fundamentals bands of the mid-IR molecular vibrational bands.
 The radiation in the NIR can interact with matter in three different ways
Diffuse Reflectance Transmission
 NIR is the most promising method for determination of blend homogeneity
and blending end point.

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Carrying out a determination :
 Ibuprofen and spray dried lactose are mixed and blending homogeneity is
determined.
Figure indicates NIRS diffuse reflectance spectra of ibuprofen (dashed
lines) and lactose in the beginning of mixing.

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Figure shows nir spectra at different time intervals indicating homogeneity is achieved at
around 3 minutes.

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 Blending profile obtained from
the entire spectral range ( ) and
over the spectral range used in
developing the calibration model
 In each case the standard
deviation of the spectra at each
wavelength of the spectral range
was first calculated. The average
standard deviation over these
wavelengths was then calculated
and plotted versus blending time.
Figure indiacates standard deviation
for determination of blending
homogeneity.

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Understanding the NIR
Figure shows change in NIR absorbance of diluents as the blending process
approaches

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NIR spectoscopy to instruments
 The NIR spectrophotometer is configured with a fiber-optic probe, which is
interfaced with the blending vessel at the point of rotation.
 NIR Spectra are acquired in real-time and using appropriate data pre-
processing and chemometric analysis, blend 'homogeneity' plots are
derived.
Figure shows Schematic representation of NIR spectroscopy with blender.

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Instrument :
 Blendalyser is the instrument
available in the market providing
NIR as an assay tool.
 Mounted on the top of blender in
rotating movement and having
sensing probes at various places
of the blender.
 Continuous and accurate
determination of blend
homogeneity can be determined.
Blender system
BlendAlyser
Connection via 4“ standard
flange using a flange
fastener

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NIR preference over other techniques :
 NIR works at the speed which can be less than one minute per
measurement.
 Capability to measure samples at a single point or at multiple locations
either inside or outside the blender
 Companies, is a challenging approach intended to assist the progression
of real-time or parametric release and quality-by-design concepts by
providing an opportunity to move from the laboratory-based besting to
document quality paradigm to a continuous quality assurance paradigm
 NIR spectroscopy may be one of the major PAT tools, since these
techniques are well-suited for at-line, in-line and on-line measurements.
 FDA announced NIR spectoscopy as the PAT initiative and also prefers
NIR results over the conventional results.

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Limitations of NIR :
 The majority of overtone peaks observed in a NIR spectrum arise from the
X-H stretching modes. They are between 10 and 1000 times weaker than
the fundamental bands so NIR is usually a weak signal, except for water,
 There is a limitation to the sensitivity of this method for high potency drug
formulations where drug content may be below 1% wrw in the mixture.
 The method requires require intense data pretreatment and chemometric
data analysis for method development

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Laser induced fluorescence technique :
 Laser-induced
fluorescence
(LIF).technique to
monitor homogeneity
of solid powder
mixtures during
component blending.
 Figure shows
schematic
representation of the
LIF techinques.

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Continue..
 The sensor uses an argon laser as the excitation light source.
 The laser beam is directed into a fiber-optic cable connected to the
Photosensor Module containing the lens and the detector Photomultiplier
tube.
 Inside the photosensor module, a dichroic mirror reflects the laser beam at
90 degrees to the sample.
 The fluorescent signal that is emitted from the sample is collimated by the
lens and passes through the dichroic mirror and an emission filter the
detector.
 Signals are converted to voltage and recorded by which is interfaced to a
computer
 Reflected Light is prevented from reaching the detector by the dichroic
mirror and the emission filter.

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Determination of blend uniformity :
 Triamterene is the active pharmaceutical ingredient and Direct compaction
anhydrous lactose are used in all experiments.
 Changes in bulk density of the powders in the blender corresponded
to a proportional change in LIF signals.
Figure shows effect of bulk densities on LIF signals.

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Figure shows data acquisitions for lactose and triamteren in LIF signals.
As the number or rotations increasing there is decrease in LIF signals which
become constant after a certain rotation which can be assumed as blending
end point.

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Figure indicates sensitivity of LIF to the location by indicating data from top and
the bottom of the blender.
• When the API was loaded at the bottom, the initial signal was high due to close
proximity of the LIF sensor near the bottom.
• When loaded on top of the blender, the initial signal was low since the sensor
was responding only to lactose during the first few rotations.
• In both cases, the LIF signals reached an equilibrium state of blend homogeneity
at the same value with signal deviations of less than 5%

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Online measurement :
 NIR spectroscopy and LIF technology gived on line measurement
for the blending homogeneity and blending end point.
 There is a large (Factor of 10-15) reduction in cycle time of blending
when online measurement are used because there is no need for
sample collection, assay and data collection.
 There is a large variability reduction in blend process development
time and process becomes more accurate and economical.

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Summary :
 As we have seen mixing is very important unit operation in
pharmaceutical manufacturing; in which determination of blending
time and achieving blending uniformity is formost.
 Conventional methods are having their own disadvantages which
turns manufacturers to the expensive online determination
techniques.
 FDA’s PAT initiative, accuracy in the results and time saving will
make these relatively expensive methods the choice of
manufacturers in near future.

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Thank you…