Pharmaceutical Engineering: Optimization of a Pharmaceutical … · 2020-02-18 · 1 Pharmaceutical Engineering: Optimization of a Pharmaceutical Formulation Michelle Bai [email protected]

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Pharmaceutical Engineering: Optimization of a Pharmaceutical

Formulation Michelle Bai

[email protected]

Melissa Gordon

[email protected]

Amolika Gupta

[email protected]

Aditya Kommi

[email protected]

Abstract

The effects of magnesium stearate

(MgSt) and shear stress on flow properties

and hydrophobicity are not well known.

Blends with different concentrations of

magnesium stearate and varying amounts

of shear were tested using three different

procedures: the FT4 Rheometer test, a tap

density analyzer, and the Washburn

method, to better understand the relation of

lubricant concentration, amount of shear,

hydrophobicity, and flow properties. The

Freeman Technology FT4 Powder

Rheometer data showed that the blend with

0.00% MgSt concentration had the poorest

flow properties and the 2.00% MgSt blend

had the best flow properties. The tap

density test revealed no correlation

between flow properties and MgSt

concentrations or amount of shear,

however these results may not be accurate

due to limited number of trials. The

Washburn method shows that increasing

the amount shear stress correlates with an

increase in hydrophobicity and vice versa.

Similarly, the Washburn method showed a

clear correlation between the concentration

of MgSt and hydrophobicity.

1. Introduction

The majority of pharmaceutical

products are solid dosage forms, making

the physical and chemical properties of

powders an important focus for the

pharmaceutical industry. The properties

of the multiple powder components that

go into any pharmaceutical formulation

affect both the manufacturing process and

the overall quality of the final product.

These may also affect the drug’s

solubility, the critical quality attribute

that ultimately determines when, where,

and how quickly the drug dissolves in the

body. This changes the bioavailability

and the therapeutic effectiveness of the

drug.

Two specific properties that will be

the focus of this project are the

concentration of the lubricant magnesium

stearate in the blend as well as the shear

applied to the lubricated powder blend;

however, little is known about how these

affect both hydrophobicity and flow

properties, which affect solubility and

processability respectively.

To gain a better understanding of

these relationships, five powder blends,

comprised of varying concentrations of

the lubricant MgSt and the filler lactose,

were sheared to three differing amounts.

By analyzing these properties, a clearer

correlation between the aforementioned

properties, hydrophobicity, and flow

behaviors may be established, thereby

shedding more light on factors that

should be considered in the

manufacturing of tablets.

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2. Background

Pharmaceutical products are

comprised of two fundamental types of

components: the active pharmaceutical

ingredients (API) and excipients,

typically in the powder form. The API is

the substance that ultimately leads to a

physiological response associated with a

desired therapeutic effect. Additionally,

excipients include a multitude of inert

substances that serve as fillers,

flavorings, binding agents, and

lubricants.

2.1 Materials Utilized

For this particular project, APIs were

excluded from the blends for safety.

Instead, only excipients, specifically

lactose, which serves as a filler, and

magnesium stearate, which serves as a

lubricant were a part of the formulations.

Lactose, a sugar commonly found in

dairy products, gives the tablet most of its

volume. This fact not only eases the

manufacturing process, but it also eases

ingestion1. Lactose is physically a fine,

white powder. Another excipient utilized

in this lab was magnesium stearate, a

lubricant used ensure that tablets are

easily ejected from the machinery.

2.2 Final Product Quality Attributes: Hydrophobicity and Flow Properties

Both hydrophobicity and flow

properties affect the overall quality of the

product. Specifically, hydrophobicity

can affect the release rate of the drug in

the body, determining its effectiveness.

Flow properties are also critical in

optimizing a pharmaceutical formula:

they are how well the powder can move

and are dependent on a multitude of

factors, such as particle size and particle

composition. However, flow properties

are of more importance during the

manufacturing process, as they affect

how the powder progresses throughout

the process. Smaller particles cause the

powder to flow poorly due to more

interactions between them, such as van

der Waals interactions. Ultimately, these

prevent free movement. The opposite is

also true: larger particles cause the

powder to flow in a more fluid-like

manner.

2.3 Shearing

Shearing is the external force acting

on a substance or surface exactly parallel

to the plane in which it lies. Applying

shear force on powders reduces the

particle size so that the powder is finer. In

other words, shearing is used to achieve

de-agglomeration. Typically, shear stress

is applied to the powder with multiple

metal blades in a shear device, and the

powder particles are scraped against each

other. Varying amounts of shear may

change a tablet’s measured

hydrophobicity and flow property values.

Shearing in the laboratory is

representative of the milling process

where mechanical impact may affect

particle size reduction and dissolution

rates of the powders. While shear does

not always have an effect, the use of a

lubricant may affect hydrophobicity, so

adding MgSt to the blend requires

quantification of the amount of shear.

2.4 Using the Carr Index to Compare

Flow Properties

Also known as the compressibility

index, the Carr index is a method used to

determine the flowability of a powder.

The formula includes a ratio of the bulk

density, the density of powder before

compression, to tap density, the density

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of the powder after compression, to

produce the answer. The equation is as

follows2:

𝐶𝑎𝑟𝑟 𝐼𝑛𝑑𝑒𝑥 = 100(1 −𝐵𝐷

𝑇𝐷)

where BD represents bulk density and

where TD represents tap density.

When the Carr index is lower, the

powder has better flow properties and is

more fluid-like; the opposite is true as

well. The Carr index values are rated on a

scale: values from 5 to 15 indicate

excellent flow properties, 16 to 18

indicate fair flow, and values above 23

indicate poor flow2.

2.5 Using the Washburn Method to

Compare Hydrophobicity

The Washburn method utilizes

capillary action to measure the

hydrophobicity of a powder. When a

powder is hydrophobic, not as much

water enters the column because the

powder and water repel each other. On

the other hand, if a powder is more

hydrophilic more water enters the

column. By comparing the change in

mass of the columns and the speed that

the water enters, the relative

hydrophobicity of a powder can be

determined. The Washburn equation is as

follows3:

where t is time, m is mass, η is the liquid

viscosity, C is a constant so long as the

particle size does not change, ρ is liquid

density, γ is the surface tension of the

liquid, and θ is the angle between the

solid and the liquid. For the purpose of

this project, these constants were

considered collectively, which provided

the slope of the Washburn method curve.

2.6 Using Mohr’s Circle Analysis and

Yield Locus for FT4 Rheometer

Analysis

Mohr’s Circle analysis is a tool that is

used for quantifying powder flow

properties using the unconfined yield

stress (UYS) and the major principle

stress (MPS). The UYS is the shear stress

needed to fracture a consolidated powder

mass to initialize flow. The MPS is the

force used to consolidate the powder

mass. On a graph, the intersection of the

small semicircle, tangent to the best fit

lines, on the x-axis is the value of UYS

and the intersection of the larger circle,

also tangent to the best fit lines, on the x-

axis is the MPS (see figure 29 in

appendix). The ratio of the MPS to UYS

is flow function coefficient (FFC), which

ranks flowability on a scale of 4 to 10,

where 4 is very cohesive and 10 is better

flow6. Generally, the closer the powder’s

flow function is to the x-axis, the more

easily the powder will flow. The UYS

and MPS can also be used to determine

the strength of bridges on hoppers, used

in processing of powders and granules in

the industry. Determining the strength of

bridges may help design hoppers that rid

the blockage of powder flow4.

The yield locus is the amount of

pressure that must be applied before the

powder “yields” or begins to flow. The

data from the shear cell, which shows the

relationship between normal stress and

shear stress, was plotted to define the

yield locus, the slope of the best fit line of

the points plotted. On a scale of 0-10, the

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higher the yield locus, the more free-

flowing the powder4.

3. Methods/Experimental Design

To measure the hydrophobicity and

flow properties of the powder blends,

three tests were used: the Washburn

method to measure hydrophobicity, tap

density to measure flow properties, and

the Freeman Technology shear cell to

also measure flow properties. Five

blends, each sheared at either 0

revolutions, 160 revolutions, or 640

revolutions, were utilized in these tests.

3.1 Blending the Powders

In order to determine the effect of

different concentrations of MgSt on

hydrophobicity and flow properties, five

blends with concentrations of 2.00%,

1.00%, 0.50%, 0.25%, and 0.00% of

MgSt were made. The 4.5 L - 5.0 L V-

blender was then filled 2/3 of the way with

the 2.00% MgSt blend, determined to be

2 kg upon calculating the blend’s bulk

density. 40g of the blend was MgSt while

the remaining 1960g was lactose.

The blending speed was then set to

the setting of six, or 15.79 RPM, for 20

minutes. This process was repeated for

each of the four other blends.

The Patterson Kelley V-Blender

(refer to Figure 1) was used to uniformly

distribute the MgSt in the lactose blend.

3.2 Shearing the Blends

The blends were sheared at varying

amounts: 0 revolutions, 160 revolutions,

or 640 revolutions at 80 RPM.

For each blend, approximately

300.00g was measured and placed into

the Metropolitan Computing Corporation

shear device. Then, the device was either

run for two minutes to achieve 160

revolutions or for eight minutes for 640

revolutions. These sheared samples were

then transferred to their appropriate

Ziploc bags.

Figure 1: Pictured above is the V-blender, used in

the pharmaceutical industry to thoroughly blend

powders.

Figure 2: Depicted above is the shear device

used to add shear stress to the powder blends.

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The custom-made shear device

consists of concentric cylinders with an

annular gap. Both the inner and the outer

cylinder contain symmetric teeth. While

the inner cylinder rotates, the outer wall

is stationary and the rapid spinning of the

teeth and powders against each other

results in shear.

3.3 Measuring Hydrophobicity using the Washburn Method

To create the saturated lactose

solution necessary for the Washburn

method, a solution was created with 350g

lactose in 1400 mL of water at 40°C. In

order to maintain this temperature, the

beaker with the solution was kept

overnight on a hot plate. Additionally, a

magnetic stirring rod was placed in the

solution to ensure thorough mixing,

which allows blend to achieve

equilibrium.

The saturated solution was then

poured through filter paper, which lined a

funnel, into the Erlenmeyer flask. This

was done to remove the undissolved

lactose. A solution was used instead of

water because the super-saturated

solution would prevent any lactose in the

column from dissolving in the solvent

during the tests. The filtered saturated

lactose solution inside the beaker was

then used for measuring hydrophobicity.

The hydrophobicity of the powder

blend was determined by measuring the

rate of the saturated solution moving up a

Washburn column.

The powder blend was initially

tapped 1000 times in the Auto Tap

Density Analyzer machine to compact the

powder tightly in the Washburn column.

The powder blend was then attached to a

ring stand by means of a ring clamp and

lowered into a beaker of the saturated

lactose solution. This entire apparatus

was placed on a balance and connected to

Ohaus Explorer Pro, which measured the

increase in mass. This process was

monitored for 35 minutes and completed

for each of the 15 blends.

3.4 Testing for Tap Density and Bulk

Density

Tap density testing is used for

measuring compaction of different

blends. In order to do this, the initial

volume of a certain powder blend was

measured in a graduated cylinder. Using

the Auto Tap Density Analyzer machine,

the blend was tapped at a constant rate of

260 taps per minute. Changes in volume

were recorded at 20 tap increments for the

first 100 taps, then 50 tap increments for

the second 100 taps, and then at 100 tap

increments for the remaining 800 taps.

All 15 blends went through this process.

3.5 Using the Freeman Technology

Shear Cell to Test Flow Properties

In order to test the resistance of

powder blends to flow movement, the

Freeman Technology 4 (FT4) Rheometer

was utilized to conduct the shear test,

which measured the powder’s behavior

from no-flow to flow state.

The testing required approximately

10 grams of the powder blend, which was

placed in a vessel. This was then placed

in the machine and under a piston. Before

testing can began, the powder

experienced pre-shear conditioning,

achieved by a spinning blade that lowered

into the powder. This created consistency

in shear with each test. Then, the blending

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blade was switched for the vented piston,

which was used to apply a normal stress

of 3 kPa to the blend. After, the top half

of the vessel was opened so that the

excess powder could be removed to

ensure a consistent and exact volume.

Subsequently, the vented piston was

replaced by the shear cell piston, which

began to move at a low speed. Once it was

lowered into the powder, stress was

slowly applied and increased until the

shear cell was able to move the powder

and caused it to flow.

This test was repeated for 4 samples:

0.00% MgSt, 0.50% MgSt, 1.00% MgSt,

and 2.00% MgSt. All were sheared at 80

RPM for 160 revolutions.

4. Results and Discussion

This experiment aimed to define a

clear relationship between physiological

properties of pharmaceutical tablets, like

MgSt concentration and shear stress, and

final quality attributes of the tablets,

including hydrophobicity and flow

properties.

4.1 FT4 Rheometer Results

The FT4 Rheometer results provided

information on yield locus, flow function

coefficient, cohesion, and Mohr’s Circle

Analysis4.

Based on the results seen in the table

for the FT4 Rheometer (refer to Figure 13

in the Appendix), the powder blend with

0.00% MgSt had the lowest FFC of

3.131. The powder blend with 2.00%

MgSt had the highest FFC of 4.592. In

order from most cohesive blend to most

free flowing, the blends are ranked as

0.00%, 0.50%, 1.00%, and 2.00% MgSt.

4.2 Tap Density Results

Concentration of MgSt Amount of Shear Added

(in revolutions)

Carr Index

0.00% MgSt 0 rev 23.770 – 23.970

160 rev 26.443 – 26.643

640 rev 22.926 – 23.126

0.25% MgSt 0 rev 23.618 – 23.818

160 rev 24.900 – 25.100

640 rev 15.773 – 15.973

0.50% MgSt 0 rev 24.267 – 24.467

160 rev 22.073 – 23.073

640 rev 20.603 – 20.803

1.00% MgSt 0 rev 21.233 – 21.433

160 rev 19.324 – 19.524

640 rev 21.438 – 21.438

2.00% MgSt 0 rev 22.268 – 22.468

160 rev 20.448 – 20.648

640 rev 22.926 – 23.126

The Carr Index values for each blend

were determined using the raw data of the

tap density test, which can be seen in

Figures 6 through 10 in the Appendix. The

0.25% MgSt blend with 640 revolutions

had the lowest Carr Index value of 15.773-

15.973. The only other Carr Index value

under 20.000 was that of 1.00% MgSt with

160 revolutions. On the other hand, all of

the 0.00% MgSt samples, the 0.25% MgSt

blend with 0 revolutions, the 0.25% MgSt

blend with 160 revolutions, the 0.50%

MgSt sample with 0 revolutions, and the

2.00% MgSt sample with 640 revolutions

have Carr Index values that exceed 23.000,

the minimum value needed for a powder to

be considered poor-flowing.

4.3 Washburn Method Results

The slopes from each of the

Washburn graphs (refer to Figures 11

through 28 in the Appendix) provide the

relationship regarding the hydrophobicity

of the powder formulation that was tested.

Figure 3: The above table displays the Carr Index values

for all 15 samples. There is a 0.2 mL range for each value

to account for the uncertainty in the tap density volume

measurements.

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The blend with the highest slope is the

0.50% MgSt at 640 revolutions, which has

an R2 value of 0.8554. Conversely, the

powder with the lowest slope is the 2.00%

MgSt at 640 revolutions, and its R2 value is

0.9997.

Of all of the graphs, ten blends had

low slopes that were less than one. This

includes all five blends without shear

stress. Similarly, three blends at 160

revolutions had these smaller slopes: 0.00%

MgSt, 0.25% MgSt, and 2.00% MgSt. Two

blends at 640 revolutions experienced this

as well.

4.4 Comparison of MgSt Concentration, Shear Stress, Hydrophobicity, and Flow Properties

The blends can be ranked, in order

from least to most free-flowing, as

0.00%, 0.50%, 1.00%, and 2.00% MgSt.

It can therefore be deduced that the

presence of MgSt improves a powder’s

flow properties. The powder blend with

no MgSt does not contain any lubricant

and is hence much more cohesive. The

FFC correlates with cohesion, measured

in kPa: the lower the FFC value, the

higher the cohesion.

The results from the tap density test

show no correlation for flow properties

and magnesium stearate concentration.

This differs from other studies by Pingali,

Podczeck, and Velasco. These authors

agreed that changing the concentration of

lubricant changes flowability4.

There also appears to be no well-

defined correlation between the amount

of shear stress applied to the blends and

flow properties. Other studies by

Pingali have shown that flow properties

decrease as amount of shear increases4.

This can be explained by the fact that

shearing makes the particles in the

powder smaller, which makes it harder

for the powders to flow.

This lack of a correlation was

determined using ANOVA tests—one for

shear stress and one for concentration of

MgSt. It was determined that there were

no significant statistical differences in

Carr Index values in either case.

Therefore, there is no distinct correlation

between varying concentrations of MgSt

and flow properties or between varying

amounts of shear stress and flow

properties that can be seen from this test.

The data collected from the

Washburn Method shows there is a direct

correlation between hydrophobicity and

the amount of shear stress applied to the

blends (refer to Figures 6 through 10). As

the amount of shear stress increased, the

hydrophobicity also increased. In the

0.50% MgSt blend sample with no shear

stress, the slope was 0.9606, while the

slope of the sample sheared for 640

revolutions had a slope of 3.5504. The

increase in slope directly correlates with

hydrophobicity. This relationship was

predicted as shearing results in smaller

particles, resulting in more interactive

forces between the particles. This

increase in hydrophobicity is consistent

with other studies4.

The Washburn Method also showed a

direct correlation between the amount of

Figure 5: This table contains ANOVA values, used

to explain the lack of a correlation between amount

of shear stress and flow properties.

Figure 4: This table contains ANOVA values,

used to explain the lack of a correlation

between the concentration of MgSt and flow

properties.

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MgSt in a blend and its hydrophobicity.

For example, when comparing the

different concentrations of MgSt sheared

at 160 revolutions, the sample with 0%

MgSt had a slope of .2346 and the sample

with 1% had a slope of 1.7799. This

means that the 1% blend absorbed less

water than the 0% blend both sheared at

160 revolutions. These results also

aligned with initial predictions regarding

a direct relationship between MgSt

concentration and hydrophobicity.

However, the 2% MgSt data does not

align to this relationship. This may be

attributed to human error when making

the actual blend: specifically, an addition

of too much lactose. Nevertheless, more

data, namely, more trials, is necessary to

better identify the reason behind this

discrepancy.

5. Conclusion

There were no significant findings

from the tap density test and Carr Index.

From the data gathered, no clear

relationship could be determined between

MgSt concentration, shear stress, and

flow properties. However, this does not

mean that a relationship does not exist,

but rather, a trend may be more obvious

if more data was collected.

The FT4 Rheometer results show

that blends with higher concentrations of

MgSt had lower yield loci, lower

cohesion rates, and higher flow function

coefficients in relation to the blend with

0.00% MgSt concentration. Hence, it can

be determined that the addition of MgSt

to a blend improves flowability and thus

allows for higher productivity in an actual

processing environment.

The Washburn Method data shows a

relation between hydrophobicity and the

amount of shear applied to the blends.

There is an increase in hydrophobicity as

the amount of shear increases. Similarly,

a direct relationship exists between MgSt

concentration and hydrophobicity.

There are a few improvements that

could be made to this experiment. First,

having more time would have improved

the quality of results. Because of time

restraints, not all blends were put in the

FT4 Rheometer and only one trial could

be done for each of the other tests.

Similarly, the tap density test was

completed only once, and the lack of data

could explain the difference in results. If

there was more data, it may be possible to

see the correlation between magnesium

stearate concentrations and flow

properties that were found in other

studies, such as Pingali’s3. Finally, there

could be error in some measurements.

Equipment such as the graduated

cylinders were not very precise, which

limited the data in terms of significant

digits and could have affected the results.

6. Acknowledgements

The authors would like to thank Bill

Engisch, Sara Koynov, and Sarang Oka

for mentoring and supervising the

experiment. Additionally, the authors

would like to thank RTA Dan Hillman,

for guiding the research process, Ilene

Rosen, the director of Rutgers

Governor’s School of Engineering and

Technology, and Jean Patrick Antoine,

the assistant director of the Rutgers

Governor’s School of Engineering and

Technology. The authors would also like

to thank Rutgers University, the State of

New Jersey, Morgan Stanley, Lockheed

Martin, Silverline Windows, South

Jersey Industries, Inc., The Provident

Bank Foundation, Novo Nordisk, and the

GSET alumni community for sponsoring

the New Jersey Governor's School for

Engineering and Technology.

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References 1S. Oka, “Intro to Dosage Forms and

Excipients” Lecture Notes, Rutgers,

Summer 2014 (unpublished) 2“Particle & Powder Density, Index

and Carr Ratio,” Escubed Limited,

<http://www.escubed.co.uk/sites/default/file

s/density_measurement_(an006)_carrs_inde

x_and_hausner_ratio.pdf> (9 July 2014). 3 K. Pingali et al., “Evaluation of

Strain-Induced Hydrophobicity of

Pharmaceutical Blends and Its Effect on

Drug Release Rate under Multiple

Compression Conditions,” Drug

Development and Industrial Pharmacy 37,

428-435 (2011).

4 "Volution Flow Therapy," Mercury

Scientific Incorporated, 2012,

<http://www.mercuryscientific.com/instrum

ents/volution-flow-theory> (24 July 2014).

5 K. Pingali et al., “Evaluation of

Strain-Induced Hydrophobicity of

Pharmaceutical Blends and Its Effect on

Drug Release Rate under Multiple

Compression Conditions,” Drug

Development and Industrial Pharmacy 37,

428-435 (2011).

6 R. Freeman, “Measuring the Flow

of Properties of Consolidated, Conditioned,

and Aerated

Powders — A Comparative Study Using a

Powder Rheometer and a Rotational Shear

Cell,” Physics International 174, 25–33

(2007).

http://www.escubed.co.uk/sites/default/files/density_measurement_(an006)_carrs_index_and_hausner_ratio.pdf



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Appendix

Taps Volume (mL); ± 0.1 mL

0 rev 160 rev 640 rev

0 81.0 mL 77.5 mL 76.0 mL

20 74.0 mL 72.5 mL 71.0 mL

40 69.5 mL 69.0 mL 67.3 mL

60 66.8 mL 66.0 mL 65.0 mL

80 64.5 mL 64.0 mL 63.0 mL

100 64.0 mL 63.5 mL 62.0 mL

150 62.0 mL 61.5 mL 61.0 mL

200 62.0 mL 61.0 mL 60.5 mL

300 61.0 mL 60.5 mL 60.0 mL

400 61.0 mL 60.0 mL 59.8 mL

500 60.5 mL 59.8 mL 59.5 mL

600 60.0 mL 59.8 mL 59.0 mL

700 60.0 mL 59.5 mL 59.0 mL

800 60.0 mL 59.5 mL 59.0 mL

900 60.0 mL 59.0 mL 58.5 mL

1000 59.5 mL 59.0 mL 58.5 mL

Figure 6: This table shows the decreasing

volumes of the 0% MgSt blend in the graduated

cylinder. This tap density test information is

used for Carr Index.



0 78.0 mL 76.0 mL 63.0 mL

20 74.0mL 70.0 mL 59.5 mL

40 70.0 mL 66.0 mL 58.0 mL

60 67.0 mL 63.3 mL 55.0 mL

80 65.0 mL 60.5 mL 54.0 mL

100 63.5 mL 59.5 mL 54.0 mL

150 62.0 mL 58.5 mL 53.5 mL

200 61.5 mL 58.0 mL 60.5 mL

300 61.0 mL 58.0 mL 60.0 mL

400 60.5 mL 57.0 mL 59.8 mL

500 60.0 mL 57.0 mL 59.5 mL

600 59.5 mL 57.0 mL 59.0 mL

700 59.5 mL 57.0 mL 59.0 mL

800 59.5 mL 57.0 mL 59.0 mL

900 59.5 mL 57.0 mL 53.0 mL

1000 59.5 mL 57.0 mL 53.0 mL


volumes of the 0.25% MgSt blend in the

graduated cylinder. This tap density test

information is used for Carr Index.







0

75.0 mL 69.5 mL 65.0 mL

20 N/A 66.0 mL 61.0 mL

40 N/A 63.0 mL 59.0 mL

60 N/A 60.5 mL 57.0 mL

80 N/A 59.0 mL 55.0 mL

100 62.0 mL 57.5 mL 54.0 mL

150 N/A 57.5 mL 52.0 mL

200 60.0 mL 56.5 mL 51.8 mL

300 60.0 mL 56.5 mL 51.5 mL

400 60.0 mL 56.5 mL 51.5 mL

500 59.5 mL 56.5 mL 51.0 mL

600 59.5 mL 56.0 mL 51.0 mL

700 59.5 mL 56.0 mL 51.0 mL

800 59.5 mL 56.0 mL 51.0 mL

900 59.0 mL 56.0 mL 51.0 mL

1000 59.0 mL 56.0 mL 51.0 mL



0 79.0 mL 74.0 mL 63.0 mL

20 73.0 mL 68.0 mL 59.5 mL

40 69.8 mL 65.0 mL 58.0 mL

60 67.0 mL 63.8 mL 55.0 mL

80 65.0 mL 61.0 mL 54.0 mL

100 63.5 mL 59.5 mL 54.0 mL

150 62.0 mL 58.0 mL 53.5 mL

200 62.0 mL 58.0 mL 60.5 mL

300 61.0 mL 57.8 mL 60.0 mL

400 60.5 mL 57.5 mL 50.8 mL

500 60.0 mL 57.0 mL 50.8 mL

600 60.0 mL 57.0 mL 50.8 mL

700 60.0 mL 57.0 mL 50.8 mL

800 59.8 mL 57.0 mL 50.8 mL

900 59.8 mL 57.0 mL 50.8 mL

1000 59.8 mL 57.0 mL 50.8 mL





11



0 76.0 mL 73.0 mL 76.0 mL

20 71.0mL 69.0 mL 71.0 mL

40 68.0 mL 66.0 mL 68.0 mL

60 64.5 mL 63.0 mL 65.0 mL

80 63.0 mL 61.5 mL 63.3 mL

100 62.0 mL 60.5 mL 62.0 mL

150 61.0 mL 60.0 mL 62.0 mL

200 60.5 mL 59.8 mL 61.0 mL

300 60.0 mL 59.0 mL 60.0 mL

400 59.5 mL 59.0 mL 59.8 mL

500 59.5 mL 58.8 mL 59.5 mL

600 59.5 mL 58.0 mL 59.0 mL

700 59.0 mL 58.0 mL 59.0 mL

800 59.0 mL 58.0 mL 59.0 mL

900 59.0 mL 58.0 mL 59.0 mL

1000 59.0 mL 58.0 mL 58.5 mL

Figure 10: This table shows the decreasing volumes

of the 2.00% MgSt blend in the graduated cylinder.

This tap density test information is used for Carr Index.

Concentration of

MgSt

(%)

Revolutions Variance of

mean

Mean of

Variance

0 160 640

0% 26.543 23.871 23.026

0.25% 23.718 25 15.873

0.5% 24.304 22.973 19.365

1% 21.333 19.424 21.538

2 22.368 20.548 23.026

Mean 23.65 22.36 20.57 2.40479

st dev 1.99 2.32 3.02

variance 3.95 5.38 9.13 6.16

Figure 11: This table describes the calculations needed to determine the F value of the ANOVA

test.

12

Figure 12: This table describes the calculations needed to determine the F value of the ANOVA

test.

Shear Blends

Material

and Batch

Cohesion

(kPa)

UYS

(kPa)

MPS

(kPa) FFC

2% MgSt 160

Rev_25mm_Shear_3kPa

2% MgSt

160 Rev 0.32 kPa 1.19 kPa 5.47 kPa 4.59

1% MgSt 160 Rev

3_25mm_Shear_3kPa

1% MgSt

160 Rev 0.38 kPa 1.29 kPa 5.37 kPa 4.15

0.5% MgSt 160

Rev_25mm_Shear_3kPa

0.5% MgSt

160 Rev 0.39 kPa 1.37 kPa 5.48 kPa 4.00

0% MgSt 160

Rev_25mm_Shear_3kPa

0% MgSt

160 Rev 0.51 kPa 1.81 kPa 5.66 kPa 3.13

Figure 13: This table displays the different values for determining flow properties of the different

samples of blends tested in the FT4 Rheometer.

Shear

(Revolutions)

Concentration of MgSt (%) Mean St Dev Variance

0% 0.25% 0.50% 1.00% 2.00%

0 26.54 23.72 24.30 21.33 22.37 23.65 1.99 3.95

160 23.87 25.00 22.97 19.42 20.55 22.36 2.32 3.95

640 23.03 15.87 19.37 21.54 23.03 20.57 3.02 5.38

Variance of

Mean

2.40

Mean of

Variance

6.16

13

Figure 14: This graph contains the best fit line of the blend sample with 0% MgSt, sheared at 0 revolutions.

The slope, 3.7008, represents the speed at which the water moved up the Washburn Column.

Figure 15: This graph contains the best fit line of the blend sample with 0% MgSt, sheared at 160

revolutions. The slope, 0.2318, represents the speed at which the water moved up the Washburn Column.

y = 0.2924x + 0.4023R² = 0.8974

y = 9.1195x - 52.068R² = 0.9909

0

5

10

15

20

25

30

35

40

45

50

0 2 4 6 8 10 12

Tim

e (

min

ute

s)

Mass^2 (g^2)

Washburn Analysis Graph for 0% Mgst at 0 rev

y = 0.2346x + 4.8914R² = 0.98

0

5

10

15

20

25

30

35

40

45

50

0 20 40 60 80 100 120 140 160 180

Tim

e (

Min

ute

s)

Mass^2 (g^2)


14

Figure 16: This graph contains the best fit line of the blend sample with 0% MgSt, sheared at 640


Figure 17: This graph contains the best fit line of the blend sample with 0.25% MgSt, sheared at 0


y = 0.919x - 0.2664R² = 0.9926

-10

0

10

20

30

40

50

60

70

0 1 2 3 4 5 6 7

Tim

e (

Min

ute

s)

Mass^2 (g^2)


y = 0.5538x + 0.2341R² = 0.9991

0

5

10

15

20

25

30

35

40

0 10 20 30 40 50 60 70

Tim

e (

Min

ute

s)

Mass2 (g2)

Washburn Method Graph for 0.25% Mgst at 0 rev

15


revolutions. The slope, 0.5538, represents the speed at which the water moved up the Washburn

Column.


revolutions. The slope, 3.6894, represents the speed at which the water moved up the Washburn

Column.

16



Figure 21: This graph contains the best fit line of the blend sample with 0.5% MgSt, sheared at

160 revolutions. The slope, 2.0065, represents the speed at which the water moved up the

Washburn Column.

y = 0.8957x - 1.541R² = 0.9857

-5

0

5

10

15

20

25

30

35

40

45

0 10 20 30 40 50

Min

ute

s

Mass2 (g2)


y = 2.0065x - 3.4234R² = 0.9926

-10

0

10

20

30

40

50

0 5 10 15 20 25

Tim

e (

Min

ute

s)

Mass2 (g2)


17


640 revolutions. The slope, 6.9958, represents the speed at which the water moved up the

Washburn Column.

y = 2.2801x - 0.2482R² = 0.953

-20

-10

0

10

20

30

40

50

0 1 2 3 4 5 6 7 8

Tim

e (

Min

ute

s)

Mass^2 (g^2)

Washburn Analysis Graph for 0.5% Mgst at 640 rev

y = 0.9606x - 28.302R² = 0.8995

0

5

10

15

20

25

30

35

40

0 10 20 30 40 50 60 70

Min

ute

s

Mass^2 (g^2)



0 revolutions. The slope 0.5592, represents the speed at which the water moved up the

Washburn Column.

18





y = 1.6346x - 5.2957R² = 0.98

-10

-5

0

5

10

15

20

25

30

35

40

0 5 10 15 20 25 30

Tim

e (

Min

ute

s)

Mass2 (g2)

Graph 1.10: Washburn Method Analysis for 1% Mgst at 160 rev

y = 3.5504x - 13.949R² = 0.9988

0

5

10

15

20

25

30

35

40

45

0 2 4 6 8 10 12 14 16 18

Min

ute

s

Mass^2 (g^2)


19





y = 0.4463x - 10.942R² = 0.9963

-50

0

50

100

150

200

250

0 100 200 300 400 500 600

Min

ute

s

Mass2 (g2)


y = 0.5059x + 1.3544R² = 0.9933

0

5

10

15

20

25

30

35

40

0 10 20 30 40 50 60 70 80

Tim

e (

Min

ute

s)

Mass2 (g2)

Washburn Method Graph for 2% Mgst at 160 rev

20



Figure 29: This graph displays the results of Mohr’s Circle Analysis. The y-intercept of the best fit line

off each sample is its cohesion. The x-intercept of the small semi-circle, tangent to the best fit lines of

each sample data, represents the unconfined yield stress (UYS) or the shear stress needed to fail a

consolidated mass to initialize flow. The x-intercept of the larger semi-circle, also tangent to the best fit

lines of each sample data, represents the major principle stress (MPS) or the force used to consolidate the

powder mass.

y = 0.1168x + 1.2588R² = 0.9997

0

5

10

15

20

25

30

35

40

0 50 100 150 200 250 300

Tim

e (

Min

ute

s)

Mass2 (g2)


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Pharmaceutical Engineering: Optimization of a Pharmaceutical … · 2020-02-18 · 1 Pharmaceutical Engineering: Optimization of a Pharmaceutical Formulation Michelle Bai [email protected]