Process Analytical Technology (PAT) assisted Crystallisation: Crystal

growth of paracetamol from its pure solutions

&

Process Analytical Technology (PAT) - Overview

Student name: Chisom Nwogbo

Student number: 19180691

Number of words: 6000

Submission date:
ABSTRACT:

Crystal growth experiment was performed at a constant temperature of 20oC. Our studied
compound is pure Paracetamol using Isopropanol as the solvent. A supersaturation ratio of
1.2 was chosen for effective crystal seed growth. A study of the effect of Seed loading on
crystal growth kinetics was also monitored with the aid of integrated PAT tools.

INTRODUCTION:

Crystallization is a purification technique with the sole aim of purifying some compounds. It
can also be defined as a separation technique where a solid phase is separated from the
mother liquor. In comparison to other separation techniques, the dispersed phase consisting of
numerous solid particles also yields the final product, that has to meet the required product
specifications. Crystallization can be also viewed as a technique to obtain solid products, via
a carefully controlled crystallization process to meet the ever-increasing demands of the
Target market on particle properties like particle size distribution, crystal shape, degree of
agglomeration, caking behavior, and purity. [CITATION HJM001 \l 2057 ]. Crystallization is both
a purification and separation technique and this is why it is widely used in the chemical
industry; notably the Pharmaceutical and Food industries. In the Pharmaceutical Industry,
crystallization is a key unit operation for the separation and purification of intermediates and
active pharmaceutical ingredients, while in the Food industry, Crystallization determines
Food quality and shelf life. The Pharmaceutical industry relies on Crystallization for the
purification of several API compounds like Ibuprofen, Aspirin, Diazepam, Lovastatin, etc.

Crystallization technique when compared to other separation techniques has major

advantages

 High Purification (irrespective of the impurity concentration in starting compound)

 Lower working temperature and Energy requirement as opposed to distillation and
evaporation
 Cost-effective since it requires less energy
 The unit operation is easy to set up and maintain.
Crystallization occurs via two major routes Nucleation and Crystal Growth. In the
crystallization process, the liquid must attain a level of supersaturation or supercooling. Once
a critical supersaturation has been achieved or better still exceeded, nucleation occurs.
Nucleation involves the formation of crystalline solids from the supersaturated liquid state.
Upon the formation of the nuclei, the growth of product-sized crystals is induced through
additional molecules into the crystal lattice. Crystallization proceeds until equilibrium is
achieved between the liquid and crystalline states and an equilibrium phase volume (of the
crystal) is produced[ CITATION Har01 \l 2057 ]. Primary Nucleation is the early formation of
crystals induced Solely by Supersaturation in the absence of any other Crystals.
Pharmaceutical companies often go for nucleation as a means of purification when the
product contains a lot of Impurities via recrystallization but Nucleation suffers from fine
particles (<um, 50-100um) and this is not desired because fine particles are difficult to filter,
Fine particles affect flow properties and Nucleation also produces undesirable broad size
distribution. Crystal growth is preferred as its particles are larger and this ensures easy
Filtration, drying and flow properties. Additionally, In a crystal growth process for formation
of Crystals, Polymorphism, enantiomers and agglomeration can be controlled.
Polymorphism is a common phenomenon of crystalline materials. It describes the ability of a
substance to exist as two or more crystalline phases that have different arrangements of the
molecules in the solid state but are otherwise identical in terms of chemical content. It should
be noted that ‘arrangement’ here includes not just the packing and orientation of molecules
that may differ, but also their conformations — even if the packing is similar, if two crystals
just differ in terms of the molecular conformations adopted then they are polymorphic.
Different polymorphs of a compound may have different physical properties, so bringing
either advantageous or deleterious consequences[ CITATION DDL17 \l 2057 ]. A good example is
Ritonavir used in HIV/AIDS Treatment. Form 1 possesses higher bioavailability and
solubility and form two possess lower solubility and bioavailability. The desired
polymorph(Form one) can be selectively grown via Crystal growth. The separation of
enantiomers is of great interest to the pharmaceutical industry since more than 50% of
pharmaceutically active ingredients are chiral, and 9 of the top 10 drugs have chiral active
ingredients. One particular enantiomer is usually preferred over the racemic
mixture[ CITATION Yal08 \l 2057 ]. The importance of chirality in the pharmaceutical industry
has been widely recognized. It is well established that one enantiomer generally exhibits
biological activities different from those of the other enantiomer because the target receptors
or enzymes are chiral. In some cases, the inactive enantiomer can even elicit undesirable side
effects, which can be avoided by the development of the pure enantiomer rather than the
racemate[ CITATION Yal08 \l 2057 ]. The desirable racemate can be crystallized by seeding the
supersaturated solution with crystals of that particular racemate. A good example is a
Zopiclone which is racemic mixture with an active and inactive Enantiomer, The active form
which is called Eszopliclone is used in treating Insomnia.

SOLUBILITY AND META-STABLE ZONE WIDTH

The concept of crystallization cannot be understood without proper knowledge of Solubility

and Meta-Stable Zone Width. Solubility provides insight into why crystals grow. Solubility is
defined as the maximum amount of a crystalline compound that can be dissolved in a specific
solvent system at the given process conditions, of which the temperature is often the most
influential parameter[ CITATION Bha17 \l 2057 ]. In-order to grow crystals, it has to exist in a
Super-saturated solution and this Solution cannot be prepared without information about the
Target API Compound’s Solubility Concentration limit. At the solubility limit, the solid
phase will remain in the liquid. For further explanation let’s assume we have some API
compound with 40g/l and this solution is heated to 40 degree Celsius and the solubility
concentration(C*) at that temperature is 20g/l. This means we cannot dissolve more than this
amount (20g/l) at 40 degrees centigrade. Even if the solution is left till t= infinity, it will not
dissolve more than 20g/l because it is at its solubility limit.
 Fig 1: Solubility Curve Diagram [ CITATION Des18 \l 2057 ]

A plot of solubility vs Temperature yields the solubility curve. The solubility curve expresses
the relationship between solubility, temperature and solvent type Solubility curve increases
with respect to temperature. This graph reveals relevant information about the optimum
solvent/antisolvent, temperature, and theoretical yield for a crystallization process[ CITATION
Des18 \l 2057 ]. Solubility increases with temperature and thus the solution needs to be cooled
to create a supersaturation. In terms of Theoretical yield, given the graph above, if a saturated
solution 70g per 100g of solvent, if the solution is cooled from 70 degree Celsius to 40 degree
Celsius, 20g of product per 100g of solvent will remain in solution and 50g per 100 g of
solvent should crystallise. This creates room for effective comparison of theoretical yield to

actual yield and define the efficiency of the Crystallization.[ CITATION Des18 \l 2057 ]. Solvent
A can be seen to be the better solvent as it is high which means more material can be
crystallised per unit mass solvent, Solvent B and C has low solubility at all temperatures,
hence less yiel d of crystallisation material[ CITATION Des18 \l 2057 ]. Once the decision of a
Solvent has been made, the Solubility Curve becomes a crucial piece of information used to
design an optimum crystallization process. This will be discussed further in the Metastable
Zone Width
 Fig 2: Meta-stable Zone width([CITATION Tec19 \l 2057 ]

The Metastable-Zone Width is commonly referred to as a Crystallization Treasure Map or

guide, and this is because it gives information on how we can control a Crystallization.
Metastable zone-width is the reason a supersaturated solution stays in the liquid phase
without the formation of crystals or solid. it is a function of solute/solvent and process
conditions process. The metastable zone width is defined as the difference between the
solubility curve (clear points) at Tsat and the metastable limit curve (cloud points) which
occurs at the temperature at which crystals are detected under a constant cooling rate. At a
temperature heated beyond Tsat, the solution containing our target API compound is clear as
it is completely dissolved, and the Turbidity meter will read zero Solid concentration-The
Turbidity meter gives information about the optical density of the solution. Once the solution
is cooled from that temperature to Tsat, and then progressively cooled at a predetermined
cooling rate below Tsat, it will be observed that at a certain temperature, the solution turns
turbid or cloudy. This prompts a new reading on the Turbidity meter. At the Metastable Zone,
the solution remains clear as there is no formation of a solid phase. The solid phase starts to
occur only at the point of the Metastable limit curve which is the cloud point or point of
Nucleation.

Controlling the Crystallization process is very important in the Industry. It is done to control
the particle size and keep track of the number of particles. At the Point of Nucleation,
Crystals formed aren’t desirable in the Industry due to reasons already stated in this text.
Therefore, there is a need to identify process conditions for Crystal Growth without the
formation of Nuclei. This process for Crystal Growth in the absence of Nucleation can be
achieved by cooling the solution at a steady rate from Tsat to a temperature very close to the
solubility curve, while if Nucleation is the preferred route for Crystallization, the limit of the
Meta-stable Zone will be chosen for working Operation. The steps involving growing crystals
is to perform one batch of nucleation crystallization experiment to obtain crystals of varying
size fractions(Crystal Size Distribution), these crystals are then filtered, dried, and undergoes
a sieve analysis. A particular size fraction is taken after sieve analysis. Once the solution is
cooled from Tsat to a temperature close to the solubility curve, a Supersaturated solution is
created. The chosen size fractions of crystals formed from nucleation are then added into the
supersaturated solution. The Industry determines the mass of nucleated crystals to be added
into the Supersaturation to grow Crystals by gaining knowledge of the amount that can be
theoretically crystallized and adding 3% of that amount as nucleated crystals. Once these
crystals are added to the already saturated solution, the crystals will grow until C=C*
 SUPERSATURATION

Crystallization is a powerful purification technique that is driven by supersaturation.

Crystallization is also drive by Mass Transfer but this phenomenon is not enough to induce
crystal formation. The chosen Solvent for Crystallization will continue to accommodate a
solute when solution concentration is less than solubility concentration. Hence,
Crystallization can only occur when the concentration of the solution ( C ) is higher than the
Solubility Concentration ( C* ), such a Solution is termed a Supersaturated Solution.

Purification of API compounds is also facilitated by supersaturation. In a Saturated solution

consisting of solute molecules or API which is associated with some impurities and dissolved
in a solvent, the solute concentration in that solution will be equal to the solubility
concentration(C=C*), Upon cooling, a supersaturation is induced with respect to the target
API compound(which remains in the supersaturated state) while the impurities remain in
solution. The crystals which contain the targeted API compound are then separated from the
impurities via Filtration.

Supersaturation also plays a major role in the rate of Crystallization. The higher the Initial
Supersaturation, the faster the crystallization rate, and this because of a decrease in the
Induction time which is the time at which all of the molecules present in the Supersaturated
solution come together in an attempt to fit and form clusters. The degree of supersaturation
can be expressed via Supersaturation ratio S = C/C* which is the solution concentration
divided by the solubility concentration at the temperature where turbidity occurs. At a
Supersaturation ratio greater than 1.5, the tendency of Crystal formation via Nucleation is
high. It can also be expressed as S= ΔC = C-C|*

CRYSTAL GROWTH EXPERIMENT

The Crystallization experiment was monitored with PAT tools(FTIR-Metler Toledo,

FBRM-Metler Toledo, PVM-Metler Toledo
Reactor = Optimax 1001 Metler-Toledo

Solubility of Paracetamol at 20C = 63.33G/750ml of Isopropanol

Working temperature = 20oC

Supersaturation ration = 1.2

Agitation speed = 3500rpm

The solubility of paracetamol at 20oC is 63.33g/750ml of Isopropanol.

To create a Supersaturation ratio of 1.2 74.06g of paracetamol in 750 ml of isopropanol

is added into the crystallizer and the crystallization is performed at a working
temperature of 20oC.

During the course of the crystallization Annotations were made to keep track of the actions
made during the experiment. PAT can monitor the entire process but it cannot monitor
actions made during the experiment.

The reactor was cleaned and dried. The Pat Tools were also cleaned and configured.

 76.04g of paracetamol(99.9 purity) was accurately weighed and added to the

crystallizer.
 750ml of Isopropanol(HPLC Grade) was added into the crystallizer
 The reactor was closed and the PAT tools were connected. The PAT tools used:
FTIR-Metler Toledo, FBRM-Metler Toledo, and PVM-Metler Toledo.
 The iControl 5.5 is used to send and receive information to the reactor, iC IR is used
to communicate with the IR Probe, iC FBRM is used to communicate with the FBRM
PAT tool, iC PVM 7.0 is used to communicate with the microscope.
 In the ic FBRM GUI(Graphical User Interface), the particle count reads zero because
all particles are settled at the bottom of the reactor as the crystal Growth experiment is
yet to begin.
 In the ic IR GUI the peak height at 1516 cm-1 corresponds the concentration of
paracetamol(Beer Lambert), this peak height is monitored to see how it changes in
respect to time
  The iControl5.5 GUI is launched to set up the Standard Operating Procedure within
the rector.
 The stirring speed is set to 350rpm TP provide agitation.
 The reactor temperature is set to 50oC and this reactor temperature was maintained
for 45 minutes.
 After 45 minutes elapsed, the solution was cooled to 20degree(Tw)
 After cooling to 20Oc, a wait time of 48 hours was set.
 After 48 hours elapsed, seed loading of 80%(theoretical yield * 0.8) was introduced
into the crystallizer.
 The second experiment was then repeated using the same Standard working procedure
with a seed loading of 50%

GRAPH OF EXPERIMENT 1

78

76

74
50 % seed loading
C, g/750 mL of IPA

72 80 % seed loading
70

68

66

64

62

60
0 200 400 600 800 1000 1200 1400 1600 1800
Time, min

Fig 3

Fig 3 shows a deviation from expected results. In expected results, the depletion
concentration of paracetamol dissolved in solvent is high with high seed loading and slower
with low seed loading. But, in the figure above the depletion of paracetamol concentration
iwith 50% seed loading is seen to be almost similar with 80% seed loading with 80% seed
loading being slightly slower. The reason for this deviation can be linked to secondary
nucleation occurring in the first experiment where the crystallizer was loaded with 50%| seed
loading. Secondary nucleation is the birth of new crystals in the presence of parent crystals of
the same substance[ CITATION DrM18 \l 2057 ].The presence of these secondary nucleated
crystals means the number of crystallizer will increase. Consequently, the mass transfer of
paracetamol in the supersatuirate solution to the crystals will increase. Secondary nucleation
might have occurred due to some external disturbances or the presence of some unwanted
impurities in the solution.

14

12
DC,g crystallised/750 mL of IPA

10
50 percent seed
8 loading
80 % seed
6 loading

0
0 200 400 600 800 1000 1200 1400 1600 1800
Time, min

Fig 4 Mass crystallized vs Time

In Figurer 4, at t=0, no crystallization occurs. Then within 200 minutes there is a rapid
increase in the mass crystallized. About 10g of paracetamol is crystallized within that
timeframe. Several hours elapsed before a mass crystallization of 10-12g occurred. And
reached saturation point.
 1.2
1.18 50% seed loading
1.16 80% seed loading
1.14
1.12
S = C/C*
1.1
1.08
1.06
1.04
1.02
1
0 200 400 600 800 1000 1200 1400 1600 1800
Time, min

Fig 5

Figure 5 also expresses similar deviations from expected results. In expected results, the
Supersaturation ratio should be consumed slowly with a seed loading of 50% but with a seed
loading of 80%, the supersaturation should be consumed much faster. But in figure 5, the
supersaturation ratio is consumed almost at a similar rate for both cases of seed loading with
80% being slightly lower. The reason for this deviation can also be linked to secondary
Nucleation as discussed in figure 3.

1200

1000
qe, g crystallised/g of seed mass

800
50% seed
loading
600

400

200

0
0 200 400 600 800 1000 1200 1400 1600 1800
Time, min

Fig 6 Amount of crystals transferred per unit mass of seed

Secondary nucleation

132 500

450
122
400
112 350
C, g/750 mL of IPA

Particle counts
300
102
250
92
200

82 150
50 % seed loading < 10 microns 100
72 10-100 microns 100-1000 microns 50

62 0
0 200 400 600 800 1000 1200 1400 1600

Time, min

Fig 7 Particle count vs Time(50% seed loading)

In figure 7, due to secondary nucleation occurrence in the first experiment done with 50%
seed loading, the particle count for particles less than 10 microns steadily increased. A slight
increase in particle count for particles within 10-100 microns was also observed. In the
absence of secondary nucleation, the particle count should remain constant.
 132 500

450
122
400
112 350
C, g/750 mL of IPA

Particle counts
300
102
80 % seed loading < 10 microns 250
92
10-100 microns 100-1000 microns 200

82 150

100
72
50
62 0
0 200 400 600 800 1000 1200 1400 1600
Time, min

Fig 8 particle count vs Time(80% seed loading)

Figure 8 represents particle count vs time in the second experiment of 80|% seed loading.
There is no secondary nucleation in this experiment and as a result, the particle count for all
range of particle microns remained constant throughout the crystallization process.
Additionally, a slight increase is observed in the particle count for all particle microns range
before it remains constant. This occurs because after the crystallizer is seeded, the seeds will
slightly agglomerate, and upon agitation from the impeller, breaks into single particles. After
some minutes, the real count will be detected by the FBRM and the count will become
constant.
 Figure 7 a plot of time/qe vs Time

CALCULATIONS

EXPERIMENT 1:

C= 76.04g of paracetamol

Reactor Volume = 750ml of Isopropanol

Solubility Concentration(C*) = 108g /kg of Isopropanol @ 20oC

Seed loading 50%

Seed size: 180-200um

Solubity concentration in g/kg will be converted to g/ml

C* @ 20oC = 108.78g paracetamol

Kg solvent 1

g paracetamol 2

g solvent

g paracetamol 3

L solvent

g paracetamol 4

750ml solvent

For step 1, 1kg=1000grams

108.78/1000 = 0.10878 g paracetamol

g solvent

For step 2

Density = Mass

Volume

Density of Isopropanol = 786g/l

786g = 1L

1g = x

x = 1/786 = 0.001272L

C* = = 0.10878 g / 0.001272L = 85.5158 g paracetamol

L solvent

For step 3

1L = 1000ml

If 1000ml = 85.5158ml

750ml = x

x(C*) = 64.125 g paracetamol

750ml Solvent

S= C/C* = 76.04/64.125= 1.2

Mass that be crystallized = C-C* = 76.04-64.125= 11.923 g paracetamol

750ml solvent

ΔC -> mass crystallised at any time, t, g/750 mL of IPA.

C=C 0−( ∆ C ) theoretical

Supersaturation ratio can be obtained using the formula

S = C/C*

The mass crystallised on to unit mass of seed crystals is given by

qe=(Co-C)*(V/M)

C= C0-ΔC

At t=200 secs for 50% seed loading

C@t=0 = C0= 76.048g/750ml

C*= 64.125g/750ml

ΔCtheoretical = C0-C* = 76.048g/750ml - 64.125g/750ml =11.923g/750ml

( I 0−FTIR)∗ ( ∆ C ) t h eoretical 11.923

∆ C= = 0.3624- 0.3576 * = 1.306719
I 0−I f 0.3624−0.3185

Mass Crystallized onto unit mass off seed crystal

V= 750ml

Mseeds = 0.5 *( ΔCtheoretical )= 0.5*11.923 = 5.9615g

750
qe = 76.048- 75.40723* =¿80.614g/g
5.9615
From figure 7

t 1 t
= +
qe k ϑ qm2 qm

y = mx + c

y = 0.0007x + 0.0212

slope(m) = 0.0007

intercept(c) = 0.0212

1
qm =
slope
1 g of paracetamol
qm = =1428.6
0.0007 g of seeds
 1
intercept =
k ϑ qm 2
1
Therefore, k ϑ= 2
qm ∗intercept
1 ml of solvent
k ϑ= =0.00002311
2
(1428.6) ∗0.0212 g of paracetamol∗min

EXPERIMENT 2:

All process conditions remains the same as experiment 1, with the exception of seed loading
which is 80%

At t = 200 secs for 80% seed loading

Mass Crystallized onto unit mass off seed crystal

ΔCtheoretical = C0-C* = 76.048g/750ml - 64.125g/750ml =11.923g/750ml

V= 750ml

Mseeds = 0.8 *( ΔCtheoretical )= 0.5*11.923 = 9.5384g

75.44777∗750
qe = 76.048− =47.192 g/ g
9.5384

From figure 7
t 1 t
= +
qe k ϑ qm qm
2

y = mx + c

y = 0.001x + 0.0588

slope(m) = 0.001

Intercept = 0.0588
 1
qm =
slope
1 g of paracetamol
qm = =1000
0.001 g of seeds
1
intercept =
k ϑ qm 2
1
Therefore, k ϑ= 2
qm ∗intercept
1 ml of solvent
k ϑ= =0.00001701
2
(1000) ∗0.0588 g of paracetamol∗min

CRYSTALLIZATION EXERCISE

We need to crystallise an API at 40 degree C. The solubility of this compound at 40 degree C is 100
g/L. Design a crystal growth experiment (explain what will be the mass of the API we need to add,
seed mass, how will you create supersaturation) for the following experimental conditions

: Working temperature: 40 oC

Initial supersaturation ratio, S = 1.2

Seed loading, 50%

Reactor volume: 500 mL (we are going to add 500 ml of solvent)

Density of the solvent: 786 kg/m 3 or g/

SOLUTION

CONCLUSION

PROCESS ANALTYTICAL TECHNOLOGY

“Industry 4.0 is considered a new industrial stage in which several emerging technologies are

converging to provide digital solutions”[ CITATION Rei20 \l 2057 ]. Industry 4.0 encompasses

Optimization of Information and Communications Technology (ICT), utilization of the

internet, incorporating Cyber and Physical systems(CPS) in Enterprise Architecture(EA) and

improving already existing Infrastructure[ CITATION Dju19 \l 2057 ]. In recent years, Industry

4.0 techniques has started to exert influence on the working principles of the pharmaceutical

industry and regulatory bodies has been put in place to ensure environmental safety and

wellbeing of the society[ CITATION Rei20 \l 2057 ].

“Pharma 4.0 is the term used to describe Industry 4.0 in a pharmaceutical manufacturing

setting” [ CITATION Tre17 \l 2057 ]. For many years, a vast majority of pharmaceutical

industries run their operations leaning towards Batch-processing rather than continuous

processing[ CITATION Lee15 \l 2057 ]. Batch-based operations in pharmaceutical companies are

quite inept and its concept less understood in comparison to various other chemical processes.

“It’s estimated that the pharmaceutical manufacturing industry wastes up to $50 billion per

year on inefficient processes. Various raw materials – including the active pharmaceutical

ingredient (API) – are produced at separate facilities around the world, adding to the overall

inefficiency of batch manufacturing[ CITATION Sar16 \l 2057 ]”. Additionally, the FAD states

that a recorded number of 300 drugs are short in supply and this is due to contamination that

occurs during batch-based operations[ CITATION Bab17 \l 2057 ]. Continuous manufacturing is

regarded to have better prospects than batch manufacturing in the pharmaceutical industry as

it offer lower rates of inefficiency, increases manufacturing flexibility and improves overall

quality by incorporating modern Process Analytical Technology into the manufacturing

process to ensure a controlled process[CITATION Vic19 \l 2057 ]. The incorporation of Process

Analytical Technology can be readily achieved as “continuous processing equipment operates

primarily at a steady state, making it an ideal fit for automation and process monitoring via process

analytical technology (PAT).”[ CITATION IRE20 \l 2057 ]. Additionally, there is a demand on the

pharmaceutical industry by the Federal Government to improve the quality of drugs, eliminate drug

shortages and increase the affordability of drugs for medical patients, this facilitated the approval of
continuous process by the FDA(Food and Drug Administration) as it entails “Quality by design” and

Process Analytical Technologies[ CITATION IRE20 \l 2057 ]. QbD (Quality by Design) is a new,

scientific approach to product design that formalizes it, automates manual testing, and simplifies

troubleshooting. It employs a systematic approach to ensure consistency by gaining a comprehensive

understanding of a finished product's compatibility with all of the components and processes involved

in its manufacture. Rather than relying solely on finished product testing, QbD offers information

early in the production process. As a consequence, a quality problem can be thoroughly investigated

and the source of the problem easily found[CITATION Dey18 \l 2057 ]. Although QbD and PAT are

typically associated with continuous processing, they can find applications in batch manufacturing

and provide significant benefits. As a result, the use of these quality control tools does not push or

hurry batch manufacturers into unchartered territories, but rather encourages them to accept a

continuous production plant after experiencing the benefits of PAT in a batch manufacturing

phase[ CITATION ADA19 \l 2057 ]. Moreover, PAT is capable of transforming a batch process into a

continuous process by providing continuous, real-time quality information. This allows for regular

quality checks along the way, eliminating the need for a final quality check before releasing a batch.

Manufacturers can "stream in" and "stream out" enough raw materials and finished goods to satisfy

demand instead of manufacturing finite amounts. The benefits of a continuous process include more

productive equipment use, increased productivity, and improved efficiency[ CITATION CHE15 \l

2057 ].

Process Analytical Technology (PAT) is a technique for designing, analysing and controlling

pharmaceutical manufacturing processes through measurements of critical quality and

performance attributes of raw and processed materials with the aim of ensuring final-end

product quality, the purpose is to develop an overall efficient process while reducing or

eliminating over-processing, improving efficiency and minimising waste[CITATION Uwe10 \l

2057 ]. Process Analytical Technology is of great importance in the pharmaceutical industry

as most API and medicine are structurally complex and develop through complex/rigorous
processes. Therefore, just End-product testing alone is not adequate to ensure top product

quality. Also, Pharmaceutical operations involves down-streaming processes which are series

of unit operations used in the separation and purification of bio-products/API at large scale

which is typically expensive [ CITATION Mis15 \l 2057 ]. Thus, PAT application in this field is

fundamental as it incorporates well-designed, rigorous process and analytical testing

strategies (which involves examination of incoming materials, in-process materials, isolated

process intermediates, drug substances, and final drug product)which enables confidence in

product quality[ CITATION Joh17 \l 2057 ] while reducing cost. In summary: Increased

process/product awareness, increased production process control, and integration of quality

into the product from the design stage are the three key benefits of introducing PAT in the

pharmaceutical industry[CITATION Sco06 \l 2057 ]. PAT offers in-depth processes management

and thus improve their robustness by on-line monitoring of some critical parameters needed

in the process. Spectroscopy (near infrared, infrared, Raman) is a popular instrument, but

other optical sensors like turbidity probes or FBRM are often used (Focused Beam

Reflectance Measurements). Analysis of large multidimensional spectral data produced by

PAT methods also requires multivariate data acquisition and data analysis tools.

Chemometrics is a chemical discipline that uses both statistical and mathematical methods

to extract and interpret data from PAT spectral instruments[ CITATION Wis15 \l 2057 ]. An

important significance of on-line monitoring of processes can be seen in Drying unit

operations. In the chemical and pharmaceutical industries, drying is an integral part of the

manufacturing process. The drying conditions and productivity have a big impact on product

quality. Furthermore, this unit operation is often the bottleneck of the entire process. As a

result, online monitoring of the drying process will result in a substantial reduction in cycle

time as well as analytical work and related costs. The monitoring of the vapor stream in the

vacuum line (headspace) and the direct measurement of the residual solvent in the powder

are the two key choices. Mass spectrometry or spectroscopy can be used to track the solvent

in the vacuum line[ CITATION Wis15 \l 2057 ].

Fig Process analytical technology (PAT) tools and techniques for tracking and controlling
downstream processes in the biotechnological and pharmaceutical industries[CITATION NNM15
\l 2057 ].

[ CITATION Kno13 \l 2057 ] discusses the application of PAT-Tools such as  NIR and Raman
spectroscopy for Process Control in Pharmaceutical film-coating applications. The method of
adding an edible paint to the surface of a pharmaceutical dosage type in order to obtain
particular benefits is known as tablet coating[ CITATION Aal13 \l 2057 ]. Non-functional
coating, functional coating and active coating are three forms of coating for the production of
solid dosages forms. The role of functional coating is to mask the offensive taste or smell of a
product and to shield the Active pharmaceutical ingredient which could be prone to
degrading in the acidic environment of the stomach and also protect the gastric mucosa
against aggressive API. Non-functional coating enhances the aesthetics of the drugs and
distinguishability for easier intake and swallowing and also offers a protective layer to
combat negative external environmental influences. An API is present in active coatings.
Film coating, sugar coating, and press coating are the three styles of tablet-coating
techniques. The most common technique is film coating, which is used on almost all new
coated items that enter the market. The deposition of a thin polymer film covering the tablet
core, normally by spraying, is known as film coating. A polymer is suspended in a suitable
liquid medium with other ingredients including pigments and plasticizers in the coating liquid
(solution or suspension). A rotating tablet bed inside a perforated pan is sprayed with the
solution. By blowing hot air through the tablet bed, the tablets are dried. The drying
conditions facilitates the evaporation of solvent from the thin film surrounding the tablet
core[CITATION Bad19 \l 2057 ]. Coat thickness is relevant in coating operations. To ensure
gastro resistance, a dosage type must have a minimum thickness and no cracks in the film. In
the absence of these conditions, the API would be released (partially) in the acid gastric fluid,
resulting in API degradation as well as irritation or damage to the stomach mucosa. The end
of the coating process is estimated from the thickness. The value retrieved from the close
monitoring of the amount of coating liquid( suspension or solution) is used as a basis to
compute the amount of dry coating mass. The surface area and density of the material to be
coated are parameters which defines or determines the film thickness. When the specified
amount of coating liquid has been absorbed, the process comes to a halt. Inevitably, there is
loss of coating liquid due to spray drying and wall adherence, the measurement is imprecise.
Hence, direct film thickness calculation or measurement during the coating process would
enhance the monitoring of the coating process. This can be achieved by integrating NIR into
the coating process as it offers in-line measurements which is a better alternative method than
at- or off-line methods because they produce timely results which possess significant intervention in

the process [ CITATION Kno13 \l 2057 ]. However,[ CITATION CCa10 \l 2057 ] reported that
Raman spectroscopy was found to be more efficient than NIRS at distinguishing
coating thickness under various process conditions. Raman spectroscopy
technology for monitoring coating process/ thickness have been reported severally
in literature.[ CITATION Wir13 \l 2057 ] utilized Raman spectroscopy to measure coat
thickness om supercell-coated tablets under various process conditions. The Figure
below resulting from the experiment compares the results of a typical in-line controlled
coating run to the reference values produced off-line. The model was successfully transferred
from laboratory scale (3 kg) to production scale (260 kg). With a relative deviation of less
than 2% for the API content in the coating, the process endpoint could be accurately
determined.
 Fig In-line API volume vs. coating time as predicted by Raman in-line data (black
squares) and calculated off-line with HPLC (red circles, mean SD, n = 10)
[ CITATION Bar11 \l 2057 ] utilized PAT tools for the production of Dihydro-1H-imidazole. A

novel approach for Cancer therapy involves the inhibition of MDM2(Oncoprotein) whose

overproduction in many tumours have been found to impair p53 activity which is a tumour

suppressor that has an important role in cell cycle regulation. Dihydro-1H-imidazole 8 is a

typical member of this class of compounds. PAT tools are incorporated in this process to

achieve an effective multikilogram scale output of Dihydro-1H-imidazole 8 by closely

monitoring the synthesis of the key intermediate 4S, 5R-7. The parameters monitored are the

phosgene levels(due to the hazardous nature of this reagent) during the synthesis of the

intermediate. The PAT tool particularly suitable for this is the infrared spectroscopy due to

this compound’s strong absorption bands at 849 and 1827 cm-1 and real time monitoring

technique.

Fig Trends in the reaction of triphosgene (2a) to phosgene (3) over time (h) during a
production run, followed by the reaction of phosgene (3) with intermediate 4[ CITATION
Bar11 \l 2057 ].

The IR PAT tool was integrated to monitor the levels of phosgene in the synthesis of the
intermediate. From the figure above, the declining trends of 2a and 3 shows the complete
break down of the phosgene precursor to phosgene and ascertains the absence of these
hazardous materials before it is transferred to the reactor for the final conversion of the
intermediate to Dihydro-1H-imidazole 8. The absence of phosgene reduces the possibility of
uncontrolled phosgene gas production in subsequent batches, which could be caused by
incompatible diphosgene exposure to the solvents and reagents involved in the process.

[ CITATION Bar11 \l 2057 ] also made application of the Lasetec FBRM to identify conditions
which could possibly minimize the risk of crystallization of the unwanted Isomer
intermediate 4R,5S-7 as 4S,5R-7 is the desired product to be isolated.

FIG Profile of the particle changes tracked (counts/sec, No Wt 10-50) in the crystallization of
product 4S,5R-7 from a methanol solution over time

The rate of crystal growth was fastest in the first 2 hours of the cooling process, as shown in
Figure 7. A second nucleation stage was observed once the temperature reached 23 C and the
crystallization appeared to have reached equilibrium. After the second nucleation stage, a
sample of the slurry was taken, and the solids were filtered and analysed using chiral HPLC.
The results revealed that the rapid crystallization of the undesirable isomer 4R,5S-7 was the
cause of the sudden growth. Values in % indicate the purity by chiral HPLC.

RAMAN SPECTROSCOPY

“Raman Spectroscopy, in its most general classification, is a form of vibrational spectroscopy, which
involves emission and absorption of infrared (IR) and visible light (as the form of light-based
interaction with the molecule)”[ CITATION Yos04 \l 2057 ]. Raman spectroscopy has a better
performance than IR, Proton NMR, mass, and UV spectroscopy, with the exception of studying gases.
However it is pricy in comparison to these other methods[ CITATION Yos04 \l 2057 ]. The vast
majority of photons dispersed or scattered at the same energy as the incident photons when light
interacts with molecules in a gas, liquid, or solid. is known as Rayleigh scattering or elastic scattering.
A small percentage of these photons, around 1 in 10,000, can scatter at a different frequency than the
incident photon. The Raman effect, or inelastic scattering, is named after Sir C.V. Raman, who
discovered it and was awarded the Nobel Prize in Physics in 1930 for his work. Raman has been used
for a wide range of applications since then, from medical diagnostics to material science and reaction
analysis. Raman enables the consumer to collect a molecule's vibrational signature, which provides
information on how it is aligned together as well as how it interacts with other molecules in the
environment. FTIR spectroscopy is more concerned with changes in dipole moment while Raman
looks at changes in polarizability of molecular bonds. Light interaction with molecules induces
electron cloud deformation. A shift in polarizability is the name for this deformation. Raman active
modes are created when molecular bonds undergo complex energy transformations that cause
polarizability to alter. When photons interact with molecules that contain homonuclear atom bonds,
such as carbon-carbon, sulfur-sulfur, and nitrogen-nitrogen bonds, the polarizability of the molecules
changes. These are examples of bonds that produce Raman active spectral bands but are not visible or
difficult to detect in the FTIR spectrum. Crystallization processes are monitored using inline Raman
spectroscopy, which reveals reaction mechanisms and kinetics. This data, when combined with
analysis tools, allows for better understanding and optimization of reactions.[CITATION Met \l 2057 ]
Commercial Raman probes for various applications, including (a) a fifteen-foot immersion probe; (b)
a conventional immersion probe, around one-foot long; and (c) a probe body for a non-contact probe
with fitting to accept different focal length optics.[CITATION Placeholder1 \l 2057 ]

MICROWAVE RESEONANCE TECHNOLOGY(MRT)

MRT technique is based off on the interaction of water molecules and evolving electromagnetic
fields. The resulting MRT signal is a band whose frequency peak and bandwidth decrease as water
and material load increases, allowing for simultaneous moisture and density measurements of solid
materials[ CITATION Lou11 \l 2057 ]. This technique utilizes the dielectric constant property of water
which is higher than most material. NIR spectroscopy technique performs a similar function like MRT
but has certain drawbacks such as it only analyses or estimates surface moisture and does not
penetrate the entire burden of material[ CITATION Ste16 \l 2057 ].

[ CITATION Joc10 \l 2057 ] Fig Main Units of Microwave Resonance Systems

NEAR INFRARED SPECTROSCOPY

Ingredients, intermediates, and finished products are all subjected to NIR spectroscopy for
compositional, functional, and sensory analysis. It's used in the food and feed, agricultural, dairy,
pharmaceutical, and chemical industries, which are constantly under pressure to produce goods that
meet consumer specifications while increasing Industry productivity and profitability. NIR may be
used for quantitative (concentration determination), qualitative (identification of raw materials,
intermediates, and finished products), and process management. It will tell you how much moisture,
protein, fat, and starch are in your food. In the infrared range, an NIR spectrometer measures
overtones and combination tones of molecular vibrations, especially asymmetric vibrations that are
intense in the near infrared range, such as stretch vibrations involving hydrogen bonds (e.g. C-H, O-H
and N-H). The light beam hits the diffraction grating, which acts like a prism to divide the light into its
constituent wavelengths. It is possible to detect the entire wavelength spectrum simultaneously
using InGaAs diode arrays. The absorption of electromagnetic (EM) radiation at wavelengths ranging
from 780 to 2,500 nm is the basis for near infrared (NIR) spectroscopy. The detector tests the
sample's transmittance and absorbance after the light interacts with it. The amount of light that
passes fully through the sample and strikes the detector is referred to as transmittance. Absorbance
is a calculation of how much light a sample absorbs. The detector detects the light passing through
the sample and transforms the data into a digital display. The frequency (f, usually in Hz),
wavelength (), and photon energy () of electromagnetic radiation are used to describe it (E).
Frequency is inversely proportional to wavelength. The energy of photons is proportional to their
frequency. The behavior of EM radiation when it interacts with atoms and molecules is determined
by the amount of energy it carries. NIR radiation, for example, has the ability to induce overtones in
molecular vibrations. Different molecule bonds absorb overtones at specific frequencies that are
specific to their structure[ CITATION Zei \l 2057 ].

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