Mixing of liquids in preparation of pharmaceutical solutions. Include both vessels and agitators in the review. Assumption - need to make batches of nasal drops from 2,000 L to 3,000 L. NOTE - This presentation was made as part of an assignment for a Course PME 530 (Introduction to Pharmaceutical Manufacturing) at Stevens Institute of Technology, Hoboken, New Jersey Prepared By - Sneha Chauhan and Kuldeep Badoniya

1. Mixing of Pharmaceutical Solutions
PME – 530
Introduction to Pharmaceutical Engineering
Stevens Institute of Technology
11/25/2013
Sneha Chauhan
Kuldeep Badoniya

2. Abstract
Nasal formulations are liquid preparations that are administered via the intranasal route. They are
used primarily for their decongestant effect on the nasal mucosa. In addition to adrenergic drugs
like Oxymethazole, Nasal preparations can be very effective in delivering nonpeptide molecules
like scopolamine as they are absorbed poorly via the oral route. This can be owed to the 20 ml
volume capacity of the nasal cavity along with microvilli that provide an enormous surface area
for the delivery of the API in formulation through the intranasal route [1].
In manufacturing of nasal preparations, mixing is a very crucial manufacturing consideration
which leads to the production of a uniform mixing of miscible liquids. A variety of mixing
equipment like paddle mixer, propeller mixer and turbine mixer are employed to attain such a
uniform mixture.
Selection of the correct equipment becomes very important to avoid liquid mixing problems like
turbulence.

3. Introduction
In order to understand the equipment involved in the mixing process, one should first have an
idea of nasal preparations and the mechanism behind their mixing. Majority of the nasal
solutions are aqueous in nature. The finished product in case of them is made isotonic to the
nasal liquids i.e. mixing of API and excipients in 0.9% NaCl [1]. Buffers are added to keep the
API stable in solution and maintain the pH range of the preparation in parallel to that of nasal
liquids (5.5-6.5) [1]. Preservatives used in nasal formulations are antimicrobial by nature and are
quite similar to the ones used for ophthalmic preparations. The concentration of API in the
formulation is close to 1% of the total 15-30 ml of packaged preparation [1]. One should be very
careful with the usage of such preparations even though many of them are available in the market
as an Over the Counter (OTC) product. Prolonged use of such preparations would lead to chronic
swelling in the nasal mucosa and aggravate the symptoms of its intended usage i.e. treating
rhinitis of common cold, hay fever and sinusitis. To avoid rebound congestion, the preparation
should be administered through a single nostril. As the congestion subsides in the nostril in
which the preparation was not administered, a complete withdrawal can be done. The subsiding
period of rebound congestion is about 1-2 weeks. In another approach, the preparation can be
substituted with a topical saline solution which will maintain the moisture level of the nasal
mucosa. In addition to this, it shall also assist the patient psychologically who are dependent on
the medication.
Mixing operations are frequently used in the pharmaceutical industry. While solutions are
prepared using two miscible liquids by mixing, the operation is also deployed for preparing
granules for tablets (solid-solid mixing), semi-solid products (solid-liquid mixing) such as
creams and jellies, emulsions (mixing two immiscible liquids with the use of an emulsifying
agent) and suspensions (dispersing solids in liquids). Mixing operations are done to ensure that
the uniformity of the solution containing two or more miscible liquids and to initiate physical
reactions like dissolution and diffusion. Pharmaceutical solutions prepared by mixing two or
more than two miscible liquids are majorly true solutions. They form a positive homogenous
mixture where the liquids get mixed by diffusion process. The properties of the resultant mixture
may change due to the surface tension or the specific gravities of the individual liquids. The ratio
in which the two/more than two liquids are mixed also has a significant effect on the resulting
mixture. Sometimes, a turbulence gets created when two miscible liquids are mixed together. It
depends on the velocity gradient between two adjacent layers of a liquid. Therefore, if a rapid
stream of liquid is introduced to a stationary liquid, the velocity gradient will be high at the
surface of the rapidly moving liquid which will eventually send portions of the faster moving
stream and send it to comparatively slow moving areas which are termed as vortex/eddy
currents. These currents remain for some time and ultimately dissipate out in the form of heat.
Conversely, some part of the slow moving liquid is drawn to the faster one due to static pressure
differences between the two.

4. Most pharmaceutical mixers are designed in such a manner that they provide such high local
velocities. Mixing as a phenomena occurs in two stages:
Localized mixing where particles of the liquids experience shear forces → which results in the
generation of a movement which is self-sufficient to take in the rest of the liquid particles
through the shear force zone resulting in a uniform mixture.
The mixing operation is accomplished with the help of a rotational device that serves as an
element of mixing providing the necessary shear forces. The device is of a particular shape so
that it produces a specific pattern inside the mixing vessel (Impeller).
Movement of a liquid inside the vessel at any point has three components of velocities and the
pattern of liquid flow inside the vessel depends on the variations among these components:
Radial – acts vertical to the impeller shaft
Tangential – acts parallel to the impeller shaft
Longitudinal – acts tangential to the rotational circle around the impeller shaft
Figure 1 – A – Tangential; B – Radial; C – Axial
[2] Image Reference: Lachman L., Lieberman H. A., Kanig J. L. (1990). The Theory and
Practice of Industrial Pharmacy (3rd
Ed.). PA, U.S.A.: Lea & Febiger.

5. The flow pattern is influenced by several factors like the form of impeller, positioning of
impeller (placed high/low in the vessel, mounted centrally or onto one side), and shaft
inclination, shape of the mixer and the presence/absence of baffles. The laws of motion and law
of conservation of mass and energy control the mixing demeanor and flow properties of fluids.
Mixing of Solutions:
Overview:
In preparation of solutions we need mixing tank /mixing vessel, baffles, draft tubes, heat transfer
surfaces and impellers. First of all we need one mixing tank in which we will mix our Active
pharmaceutical ingredient (API) along with water and in another mixing tank we will mix all the
excipients like water, preservatives, buffer salts, pH adjusting agents modifying agents, viscosity
modifying agents, suspending agents and flavors. Mixture from both the tanks is then transferred
to our main mixing tank where our main mixing process will take place with the help of the
agitators and the motor on top of the vessel. The vessel also has heat transfer tubes to maintain
the appropriate temperature of the entire vessel so when mixing takes place temperature is
maintained properly to achieve proper mixing and then cooling process takes place. And after the
mixture is cooled from here the mixture is discharged from the lower end of the vessel and is
transferred via the pump to the filling machine equipment where the filling of nasal solutions
occur and then finally capping of the nasal drops and packaging occurs.

6. Schematic Diagram of Mixing:
Figure 2 – Diagram showing Cross Section of a Mixer
[3] Reference of the diagram: http://en.wikipedia.org/wiki/Baffle_(heat_transfer)

7. Figure 3 – Parts of a Mixer
[4] Reference for the diagram and description: http://www.uni-mix.com/liquid-mixers/
http://www.armstrongpumps.com/Data/otherinfos/Links/01_04_003/baffles.pdf
Vessel:
• A vertical vessel in a cylindrical shape has the tank diameter equal to the liquid height.
• The vessel’s top and the bottom end is usually with flat or dished ends (as labelled as 2)
means curved ends or ends in the shape of the dish which is usually ellipsoidal in shape.

8. • There are nozzle for manhole (through which a person can see in), nozzle to allow to
release the mixed final product from the bottom of the vessel, nozzle for supply or
feeding of the materials, nozzle for measuring devices and for the agitators.
Baffle:
• Baffles are usually placed on the agitators in order to get good mixing with a proper flow
pattern and to prevent the vortex formation.( as labelled 26)
• They also hold the tubes together and help in heat transfer by directing the flow of the
fluid over the tubes.
• Baffles improve the process performance.
• In routine for our standard agitation four vertical baffles are provided having width of
1/10th
or 1/12th
of the tank diameter.
Draft Tubes:
Figure 4 – Draft Tubes inside a Mixer
• Draft tube is cylindrical in shape which is kept around the impeller and is placed in order
to contribute in efficient mixing by directing the suction and discharge flow patterns.
• It is usually used with the axial impellers.
• The impeller draft tube system arrangement will act as a low efficiency axial flow pump.
• They are useful in vessels which has high ratio of height to diameter.

9. [5] Reference of the link for the diagram of draft tubes:
https://www.google.com/search?
q=draft+tubes+in+mixing+tank&source=lnms&tbm=isch&sa=X&ei=I4GSUpTJNIevsQTAsYCoBg&ved=0CA
cQ_AUoAQ&biw=1517&bih=741#facrc=_&imgdii=Mf3jHFNgCjeKtM%3A%3BeC0ENwEKnqHisM
%3BMf3jHFNgCjeKtM%3A&imgrc=Mf3jHFNgCjeKtM%3A%3BphB6Up2zeyI70M%3Bhttp%253A%252F
%252Fwww.niroinc.com%252Fimages%252Fevaporators_crystallizers
%252Fdraft_tube_crystallizer_fg1.gif%3Bhttp%253A%252F%252Fwww.niroinc.com
%252Fevaporators_crystallizers%252Fcrystallization_theory_dtb.asp%3B220%3B222
Heat Transfer Surfaces:
• These surfaces for heat transfer are used for heating and cooling of the process which our
solutions to be mixed requires.
• Heat Transfer depends on:
• Surface area for the transfer of the heat.
• Temperature difference
• Heat transfer coefficient
• The turbulent flow generated by the impellers will help in improving the heat transfer
coefficient.
Impellers:
Impellers are nothing but the rotor blades which help to increase the flow of our liquids or
increase the pressure or
• On the liquid viscosity basis impellers are categorized as turbines for low viscosity
liquids.

10. • Also based on the flow patterns they are categorized as axial flow impellers and radial
flow impellers.
Axial flow impellers
• Marine propellers
• Hydrofoil Impellers
Radial flow impellers
Axial flow impellers:
Figure 5 – Axial Flow Impeller
[6] Reference of the image: http://www.google.com/imgres?imgurl=&imgrefurl=http%3A%2F
%2Fnuclearpowertraining.tpub.com%2Fh1018v1%2Fcss
%2Fh1018v1_99.htm&h=0&w=0&sz=1&tbnid=v7dRMxVXcw2J3M&tbnh=190&tbnw=200&zoom=1&doci
d=ClzbAB0cjXpAOM&ei=fKOSUonVIuXMsQSM94K4Bw&ved=0CAIQsCU

11. 1) Marine Propellers:
Figure 6 – Blade of a Marine Propeller
Speed range – 400 to 1800 rpm.
Variations in marine propeller may include instead of three bladed, four blade propeller can be
used, also with saw tooth edges for moving the liquid in a quick manner (tearing action),
perforated or blades with the holes for breaking of the lumps and for cutting into smaller pieces
(shred).
They are also used for mixers with an entry having at the side. They are placed on the shaft of
the impellers which is inclined at an angle by keeping in mind with the reference of the vessel
center line, to get the better results of the process.
2) Hydrofoil Impellers:

12. Figure 7 – Hydrofoil Impeller
• It is the impeller with high efficiency which is designed to increase and maximize the
flow of the fluid and decrease the rate of the shear.
Radial Flow Impellers:

13. Figure 8 – Cross Section of a Radial Flow Impeller
• The blade of the impeller is parallel to the axis of the impeller.
• It is effective for gas-liquid mixing and liquid-liquid mixing.
• They are used for single phase and multiple phase mixing.
• It releases the flow along the radius of the impeller.
Machines and Equipment
Paddle mixer
• It employs the use of paddles as an impeller for mixing of liquids.
• Paddle consists of a flat blade that is attached to a vertical shaft and rotates at speeds of
100 r.p.m.
• To make the blades rotate close enough to the walls of the container, they are provided
with a large surface area.
• Rotation at low speeds prevents the vortex formation.

14. Specificatio
n(L)
Volu
me
(L)
Mixing Po
wer
(KW)
Mixing sp
eed
(R/MIN))
Homogene
ous power
(KW)
Homogene
ous
speed (R/
MIN)
heating
way
BS-3000 3000 7.5 0-65 18 2890 Steam/Ele
ctric

15. Figure 9 – Paddle Mixer
[7] Image Reference: http://www.alibaba.com/product-
gs/612074335/BS_200L_Paddle_mixers_for_sale.html
Propeller Mixer

16. • They are widely used for mixing of solutions with low viscosity consisting of a rotating
shaft with propeller blades.
• They rotate at very high speed as a result of which mixing operation will be
accomplished in a very short time.
• They have a smaller diameter as compared to paddle and turbine mixer and the viscosity
range suitable for this mixer is 2-5 Pascals.
Specifications Working
Volume (L)
Actual
Volume
(L)
Equipment
Weight
(Kg.)
Cover
Power
Mpa
(Steam)
Supporting
Power (KW)
2000 2000 2400 1500 0.3 36

17. Figure 10 – Propeller Mixer
[8] Image Reference: http://www.alibaba.com/product-
gs/1432158399/JBJ_100L_propeller_mixer.html
References:
[1] Ansel H.C., Popovich N.G., Allen L.V. (2011). Ansel’s Pharmaceutical Dosage Forms and Drug
Delivery Systems (9th
Ed.). China: Lippincott Williams & Wilkins.
[2] Lachman L., Lieberman H. A., Kanig J. L. (1990). The Theory and Practice of
Industrial Pharmacy (3rd
Ed.). PA, U.S.A.: Lea & Febiger.
[3] http://en.wikipedia.org/wiki/Baffle_(heat_transfer) Components of Liquid flow
[4] http://www.uni-mix.com/liquid-mixers/

18. http://www.armstrongpumps.com/Data/otherinfos/Links/01_04_003/baffles.pdf Parts of a
Mixer, Marine Propeller, Hydrofoil Impeller, Radial Flow Impeller
[5]https://www.google.com/search?
q=draft+tubes+in+mixing+tank&source=lnms&tbm=isch&sa=X&ei=I4GSUpTJNIevsQTAsYCoBg&ved=0CA
cQ_AUoAQ&biw=1517&bih=741#facrc=_&imgdii=Mf3jHFNgCjeKtM%3A%3BeC0ENwEKnqHisM
%3BMf3jHFNgCjeKtM%3A&imgrc=Mf3jHFNgCjeKtM%3A%3BphB6Up2zeyI70M%3Bhttp%253A%252F
%252Fwww.niroinc.com%252Fimages%252Fevaporators_crystallizers
%252Fdraft_tube_crystallizer_fg1.gif%3Bhttp%253A%252F%252Fwww.niroinc.com
%252Fevaporators_crystallizers%252Fcrystallization_theory_dtb.asp%3B220%3B222 Draft Tube
[6]http://www.google.com/imgres?imgurl=&imgrefurl=http%3A%2F
%2Fnuclearpowertraining.tpub.com%2Fh1018v1%2Fcss
%2Fh1018v1_99.htm&h=0&w=0&sz=1&tbnid=v7dRMxVXcw2J3M&tbnh=190&tbnw=200&zoom=1&doci
d=ClzbAB0cjXpAOM&ei=fKOSUonVIuXMsQSM94K4Bw&ved=0CAIQsCU Axial Flow Impeller
[7] http://www.alibaba.com/product-gs/612074335/BS_200L_Paddle_mixers_for_sale.html Paddle
Mixer
[8] http://www.alibaba.com/product-gs/1432158399/JBJ_100L_propeller_mixer.html Propeller Mixer