PROJECT DESCRIPTION

BACKGROUND

Most

pharmaceutical

tablets

are

composed

of

an

active

pharmaceutical

ingredient

(API)

and

filler

ingredients

(“excipients”).

Drying

is

an

essential

step

of

the

manufacturing

process

for

an

API

and

is

arguable

one

of

the

most

delicate.

One

of

the

more

commonly

used

equipment

units

for

API

drying

is

the

bladed

mixer.

It

consists

of

a

vertical

cylinder

mixer

with

a

heating

jacket

and

an

impeller

to

mix

the

material.

This

type

of

drying

is

commonly

referred

to

as

agitated

drying.

Despite

its

widespread

implementation

throughout

the

pharmaceutical

industry,

agitated

drying

of

APIs

remains

a

challenging

step

of

the

manufacturing

process.

Simultaneous

transient

changes

in

heat

transfer,

mass

transfer,

and

physicochemical

properties

occur

during

drying,

making

it

difficult

to

understand,

optimize,

and

scale

up.

Many

issues

can

plague

the

process,

including

degradation

of

temperature-sensitive

APIs,

non-uniform

drying,

incomplete

drying,

generation

of

impurities,

loss

of

crystallinity,

agglomeration,

and

attrition.

Finding

an

optimal

protocol

that

enhances

drying

of

the

bed,

while

mitigating

the

potential

for

adverse

effects,

is

often

an

important consideration for pharmaceutical companies.

PROJECT GOALS

The

objective

of

this

project

is

to

achieve

a

more

fundamental

understanding

of

the

drying

step

during

the

manufacturing

of

pharmaceuticals.

We

use

a

combined

approach

based

on

experiments

and

simulations

to

study

and

quantify

material

flow,

heat

transfer,

and

mass

transfer

during

agitated

drying.

Based

on

our

findings,

we

aim

to

develop

scientific

conclusions

that

can

help

inform

our

industrial partner when they design their drying protocols.

SUMMARY OF STUDIES

The main challenge with drying stems from the fact that many things happen simultaneously, making it difficult to obtain a thorough understanding of the system. Our approach for this work is to decouple the problem by isolating different aspects of agitated drying and studying them individually in order to understand how each phenomenon contributes to the process. More specifically, the project is broken down into three components: material flow, heat transfer, and mass transfer. Material flow refers to characterizing particle movement in the bed, mixing, and particle breakage (“attrition”). Heat transfer involves looking at how heat flows from the hot walls to the powder bed and measuring the temperature distribution in the material. Mass transfer refers to quantifying the rate of evaporation of the solvent during drying. Studying each phenomenon individually greatly simplifies the problem and allows us to draw clearer conclusions about how the different components influence the overall process. We collaborate closely with a pharmaceutical company to discuss results and the overall progress of the project. This project leverages a combination of experiments and modeling. For the experiments, our equipment consists of a laboratory-scale bladed mixer with a heating jacket, an HMI (human machine interface), an impeller, a motor, a torque meter, a weighing scale, a condenser, an infrared camera, and a vacuum pump (Figure 1). We are interested in evaluating how different operating conditions and material properties affect drying. Typical parameters of interest include agitation speed of the impeller, fill height, particle size, material thermal conductivity, and moisture content. Our lab makes use of glass beads and a variety of different powders to understand how different materials behave. Figure 1: Bladed mixer and frame assembly In addition to the experiments, we are interested in simulating the process using discrete element method modeling (DEM) (Figure 2). DEM modeling considers each particle as a distinct entity and tracks its behavior over time. Typical data that can be extracted from these simulations include particle position, velocity, temperature, contacts, and forces. For example, Figure 3 shows how a bed of particles heats up as it is being mixed. The simulation shows how particles near the hot walls heat up rapidly while the core of the bed remains cold for a longer period of time. We are interested in using this kind of simulation to investigate how operating and material parameters influence drying. Figure 2: DEM simulation of the bladed mixer geometry Figure 3: DEM simulation of heat transfer in a bladed mixer, showing the temperatures of particles in a color scheme The overall goal is to use experiments to validate the simulation model. Once this is achieved, simulations can be used to make predictions. Some APIs are among the most expensive materials in the world so using simulations to educate the design of experiments can be very desirable for pharmaceutical companies.