1. practically applicable methods [10]. NIR spectroscopy is very

1.     INTRODUCTION:

 

I.                  
IMPORTANCE OF ANALYTICAL TECHNIQUES FOR
PHARMACEUTICALS:

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It is very important to check the purity
of the pharmaceutical products to avoid harmful toxic effects in the humans.
Hence, to remove it there should be various analytical techniques used in
pharmaceuticals. Various techniques are important   like spectroscopic and chromatographic. It is
very important the quality of drugs by various analytical techniques for better
results 1. Analytical methods is also important with environmental aspects
that pharmaceutical products should be non-toxic and free from harmful
pollutants 2. Hyphenated techniques also gives importance in analytical techniques
with pharmaceuticals such as GC-MS, LC-MS techniques 3. Some analytical
techniques like UV-Vis, flourimetric and vibrational spectroscopies is also
important for utilization in pharmaceuticals to develop fastest method and
reduction of solvents also 4. Analytical methods play very important role in
pharmaceuticals from impurities detection to conclusion of structure
identification and for safety and efficacy in patients 5. Some novel
analytical methods are also employed for the detection of   pharmaceuticals
like automatic sampling analysis, miniaturization and pattern recognition 6. Thus,
it is important to use analytical methods in pharmaceuticals with utilization
of low cost reduction and easy, optimized and eco-friendly 7.

 

II.               
IMPORTANCE OF VIBRATIONAL SPECTROSCOPY
IN PHARMACEUTICAL ANALYSIS:

Importance of vibrational spectroscopies
include NIR, Raman and mid-IR techniques in analysis in development of method
with less or no sample preparation without causing damage 8. Vibrational
spectroscopies is also useful in elucidation of structure to find molecules of
structures and their metabolites 9. It is important for qualitative and
quantitative evaluation of drugs and also have fastest technologies with
theoretically and practically applicable methods 10. NIR spectroscopy is very
important in vibrational spectroscopy because of identification of various
polymers, bulk materials, assessment of quality and versatile techniques 11. Vibrational
spectroscopy also includes green chemistry for reduction of toxic-reagent
harmful to people 12. They also includes detection of volumetric analysis and
turbidity in samples 13. It is also important in the analysis of plant
tissues, organs and cells 14. Vibrational spectroscopy is also important in
characterization of solids and crystals with chemometrics and techniques such
as PLS, TRS and LFR 15. They are applicable to identify API, counterfeit of
drugs and evaluation of tablets 16. It is also the main tools in the biologicals
to study drug interaction and various techniques such as high-throughput
screening, disease diagnosis and spectral pathology 17. Thus, vibrational
spectroscopy is useful in pharmaceutical analysis to analyze drugs and
determine the quantity of materials and substances with various techniques such
as NIR-CI, FTIR, MIR, PLS, etc 18.

 

III.            
IMPORTANCE OF NIR SPECTROSCOPY:

The importance of NIR spectroscopy
covers wider range of areas like foods, pharmaceuticals, petrochemicals and
agriculture 19. Importance of NIR chemical imaging is also important to
determine statistical information 20. Hyphenated techniques also involved in
NIR with PAT tools. It is important for identification and characterization of
solid dosage forms 21. It is also important in the manufacturing of tablet
dosage form with methodology like partial least squares 22. NIR is also
important for determination of oils and pastes 23. NIR spectroscopy is
important in pharmaceuticals because it is simple and fastest methods with no
sample preparation and involves automated sampling of any dosage forms 24. It
is also important for determination of soil to determine concentration of heavy
metals 25. They are also useful for the evaluation of meats in animals and
muscles in humans 26. NIR also has importance to various disease like
Alzheimer’s disease related to neuro-science 27. NIR method is also
applicable to develop analytical method validation in various dosage forms 28.
NIR technique is also important for glucose determination 29. They are also
important for determination of proper fruit quality and analyze through
spectral data 30. NIR is also better tool to identify raw materials and
having on-line monitoring techniques 31. Liposomes are also characterized by
NIR 32. NIR spectroscopy is also important to determine brain studies in
humans and animals 33. NIR is also applicable to energy conservation process
like biomass to determine the decomposition process, biodiesel identification
and inspecting biofuel process 34. NIR spectroscopy play a vital role in
chemometric tools to identify API and spectral data. Thus, PCA is important
component used in this methods 35. NIR is also clinically important with
various applications like newly born infants, neuronal data and evaluation of
tissue haemoglobin saturation techniques 36.

 

2.     NIR TECHNIQUE:

 

I.                  
PRINCIPLE: 24

NIR  principle is based on the method  that a material would be absorbed by  NIR energy and then  transmits or reflects into  unique pattern as per  physical and chemical characterization. Hence  NIR technique can be used for qualitative and
quantitative analysis.The wavelength range between 780 and 2565 nm and wavenumber
range 12820-3959cm-1 is the range where NIR is located. In the NIR light source
sample was irradiated and then absorbed by the  molecules only when the dipole moment is
changed due to molecular vibrations. O-H, N-H, S-H and R-H groups is having
higher dipole moment. hence they are showing strong  absorbance in NIR.Overtones
and combination of bands in various fundamental vibrations occurs in NIR  due to –CH, -NH, -OH groups are having
measurable bands of absorption which is due to multi-level energy transitions. Combination
bands also seen in polyatomic molecules with the result of same energy producing
in changing of vibrational modes. The combination bands occurs between 1900-2500
nm due to interactions takes place in vibrations. Stretching and bending
absorption takes place in NIR technique. Stretching can be defined as a changes
occurs in bond-axis and no changes occurs in bond-angle whereas bending is
defined as changes occurs in  bond-angle
and no changes occurs  in bond-axis.

 

                               Fig. 1: Electromagnetic spectrum 35

 

 

 

                       Fig. 2: Anharmonic model 35

II.               
INSTRUMENTATION: 24

Instrumentation of NIR is applicable having fastest and comfort
analysis of various samples. Instrumentation is made up of light source,
wavelength selection system, sample holder, sample presentation interface and a
detector. Fig. 3 represents the instrumentation of NIR spectroscopy:

 

 

  
Fig. 3: INSTRUMENTATION OF NIR SPECTROSCOPY. 35

 

In
light source the beam is generated and irradiation takes places and the
samples  analysis takes place. Light
source which is useful is halogen light having tungsten filament and quartz window
used to emit continuous spectrum in the ranges of 320 nm to 2500nm. Where as LEDs
(Light Emitting Diodes) is capable to emit up to 1600 nm. The halogen lamps
have requirement of wavelength selection system, while LEDs do not require this.
Samples presented is available in transmittance, transreflectance and
reflectance in the instrumentation of NIR. NIR technique is divided into two
types based on the selection of wavelength namely dispersive and non-dispersive
instruments. Monochromators are mainly used in dispersive techniques. Conventional
filters, Fourier transform (FT)-NIR type and AOTFS (Acusto-Optic Tunable
Filters) are useful for non-dispersive techniques. Detectors used in NIR
instrumentation is single-channeled detectors like PbS and InGaAs and
multi-channeled detectors like CCD’s and Array detectors to detect the sample
and obtain the spectra.

 

III.            
ADVANTAGES:

·        
Fast
and ability to detect sample very well. 21

·        
Sample
preparation is not required and on-line monitoring is possible.

·        
Reduction
in costs and reagents and used for parameters such as viscosity, density and
particle size.19

·        
NIR
technique is comfortable and used in easy to use techniques and NIR radiation
have better penetration power. 24

·        
Non-destructive,
non-contact and simple technique of analysis. 11

·        
NIR
method is accurate, automatic and easy to use for installation and maintainance.
37

·        
It
is also applicable to tablet monitoring and manufacturing process. 38

                

 

IV.            
LATEST
ADVANCEMENTS IN NIR:

 

Sr.no

Advancements

Uses

Reference

1.

Mineral
identification

Used
to identify minerals by NIR method through remote sensing

39

2.

Technique
for solid-state characterization

To
identify and monitor solid compounds, drugs and excipients

21

3.

Food
safety

Used
for detection of food sources by obtaining spectra

40

4.

Soil
determination

NIR
method is used to characterize content of copper in soils using PLS method

25

5.

Neuroscience

NIR
technique is employed with light emitting diode technique in neurological for
detection of neuronal disorders

41

6.

Plant-tissue
analysis

NIR
is involved to determine spectral information.

14

7.

Fiber-optics
biosensors

NIR
technique are equipped with fiber optics biosensing for determination of
various  bacterias and species

42

8.

Blood-glucose
monitoring

NIR
is used to analyze glucose levels with help of spectra

29

9.

Determination
of beef-quality

NIR probes are used to determine
quality of beef with visible region

43

10.

Aquaphotomics
technique

This technique is employed with NIR to
detect pollutants in water and agriculture mainly cadmium compound.

44

11.

LED
based NIR sensors for human kidney tumor diagnostics

Used for detection of cancerous cells
in kidney

45

 

 

3.    
PAT:

 

I.                  
INTRODUCTION:

Process
analytical technique (PAT) may be defined as “a system for designing and
controlling manufacturing through timely measurements (i.e. during processing)
of critical quality and performance attributes for raw and in-process materials
and also processes with the goal of ensuring final product quality into the
product and manufacturing processes and their continuous process improvement.”
46

The
strategy of PAT includes: 47

1.     
Identification
and understanding of critical parameters.

2.     
Control
of critical parameters.

3.     
Establish
safety and quality.

 

II.               
SCOPE:
48

Reduction
in batch failures.

Reduction
in time cycle.

Consistent
batches are produced

Errors
can be reduced

Automated
sampling and prevent batch rejection

 

III.            
TECHNIQUE:

At-line:
analysis carried out on premises and laboratory.

On-line:
automated sampling analysis.

In-line:
no sampling instrument required and invasive or non-invasive. 48

                                                                                                             

IV.            
PAT
GOALS :

The
goal is to designing and developing better manufacturing process for
identification of raw materials and equipment to produce consistent results of
final product.The aim of PAT is to determine product quality with proper
evaluation of products.

 

V.               
PAT
IMPLEMENTATION: 46

      PAT implementation takes place as
follows:

1.     
Identification

2.     
Monitoring

3.     
Analysis

4.     
Controlling

5.     
Reporting

 

1.      Identification:
to identify the critical parameters and characteristics of quality in the process.

 

2.      Monitoring:
after identifying the parameter monitoring takes place. Monitoring process
takes place by automated or on-line analysis to determine quality
characteristics with various analytical techniques.

 

3.      Analysis: after
monitor and identification of critical parameters analysis is done to evaluate
critical parameters including the methods to be validated and verified.

 

4.      Controlling:
after doing analysis it is necessary to control the process and result should
be within limits.

 

5.      Reporting:
report is necessary document to implement the process.

 

VI.            
PAT
TOOLS:

Various analytical tools have
been available with PAT to determine physical, chemical and chemical analysis.
46

Some tools are NIR, Raman,
titrimetric techniques and hyphenated techniques.ajptr 46

Multivariate-data
acquisition and analysis tools: this tool includes statistical tools
to develop the method and identify it.

Modern process
analyzers:
this tool provides measurements without causing damage including automated and
manual sampling.

Process and
endpoint monitoring and control tools: this tool includes identification,
designing and measurement of process and to inspect it.

 

VII.         
APPLICATIONS:

·        
Radiochemistry
48

·        
BioPAT

·        
Chemometrics

·        
Crystallization
49

·        
Blending
46

·        
Biopharmaceuticals

·        
Reaction
monitoring 50

·        
Raw-material
identification 50

 

 

VIII.      
USFDA
GUIDELINES: 51

USFDA
guidelines of PAT gives information about developing and implementing the
process. The guidelines also also helpful to the industry by viewing technical
issues and encourages about novel methods. USFDA guidelines of PAT also
includes topics of CMC and cGMP to develop and implement the novel approaches. The
guidelines also gives information about maintainance of quality of products and
motivate manufacturer to do novel advances in pharmaceutical technology. The
agency also include framework of PAT giving goals that quality of products
should be in-built and meet regulatory requirements related to validating and
handling the process of manufacturing. Hence, the goal of this guidance is to
do better understanding of product and it’s quality meet the limits as per
guidelines.

 

 

4.    
APPLICATION OF
NIR IN PAT:

 

i)                   
Tablet:

 

Tablet
is used as a PAT tool in NIR for various purposes such as in manufacturing of
tablet or solid dosage form, film coating process, determination of active
coating of low dose drug, calibration process using NIR, automated sampling
analysis and production of tablets 52-57. In blending process of powders
resonant acoustic mixing (RAM) is used as a PAT tool of NIR for in-line and
real-time monitoring 58. It is applicable to processes like automated
inspection of powders using transmittance and reflectance mode and these modes
are also useful for assay of API and tensile strength 59,60.

NIR
is also used as a PAT tool in tablet process like quality and quantity of drugs
and excipients, for monitoring roller compacter ribbon density to determine
spectral information, monitoring of multivitamin powder blend 61-63. They are
also applicable to evaluation of tablet such as hardness, dissolution process,
active content of uncoated tablet, uniformity of content, raw-material
identification for powders, etc. 64-68. They are also useful for
determination of API in tablet manufacturing by in-line process through
NIR-chemical imaging, drying process and techniques such as hot-melt extrusion
using NIR probes, PLS (Partial least square) and MLR (Multiple linear
regression) 69-72.

 

ii)                 
Biological:

 

Biological
is another application of NIR in PAT which describes manufacturing of
biological with better knowledge of production process with reduced cost. In
biological techniques such as cell-culture are involved to monitor animal-cell
and their process parameters for better quality. Thus animal cell culture is
also important part of NIR as a PAT. In biological they are also applicable for
determination of composition of biodegradable materials such as film
biopolymers and correlate with PLS method. It is also used for on-line
monitoring in manufacturing of monoclonal antibodies. 73-76

 

 

iii)               
Extraction
process:

 

NIR
is used as a PAT tool for evaluating and automated sampling of extraction
process. For e.g. Gardeniae fructus with medicinal values is used for NIR as a
PAT tool on which sample of this medicine is collected and detected by NIR by
using single PLS and done for concentration of high analytes and determine
active components. 77,78

 

iv)               
Distillation
process:

 

NIR
is used as a PAT tool in distillation which involves on-line monitoring of
distillation process by NIR and determination of spectra. 79

 

v)                 
Glucose
concentration of Chinese hamster ovary cell development:

 

NIR
is used as a PAT tool in which shake-flask model system was developed in which
prediction of glucose is done with automated inspection and spectra is
determined for cultivation process. 80

 

vi)               
Traditional
Chinese medicines:

 

NIR
is used as a PAT tool in traditional-chinese medicines for monitoring the
changes of physical and chemical properties. 81

 

vii)             
Amylose content
in rice:

 

NIR is used as
PAT tool for determination of amylose content in rice by NIR method to develop
optimize results with no variations as automated sampling tool of PAT. 82

 

viii)           
Liposomes:

 

The
application includes automated sampling analysis of freeze-dried circulated
liposomes by NIR as a potential PAT tool. 83

 

ix)               
Ground-beef:

 

The
application involves PAT methods applied to ground-beef using PLS technique and
automated sampling by NIR spectroscopy. 84

 

x)                 
Alcohol
precipitation:

 

The application of NIR as a PAT tool to
monitor alcohol precipitation in which automated monitoring takes place in
transmittance to take spectra with real-time testing quantitatively. 85

 

xi)               
 Crystallization:

 

It
includes about automated sampling by NIR and PAT tools with PLS and MVA in
crystallization process. 86

 

xii)             
Amino-acids:

 

The
application includes about uses of NIR to apply PAT tool in monitoring
hydrolysis process of amino acids. 87

 

xiii)           
Freeze-drying
process:

 

NIR
is used as PAT tool for monitoring of freeze drying process in which detection
of drying end-point is measured by NIR probes. 88

 

xiv)           
Solid-dispersion:

 

NIR
is used as PAT tool for estimation of solid dispersion by NIR spectral imaging.
89

 

xv)             
Chemo-metrics:

 

NIR
is used as PAT tool in chemo-metrics for determination of qualitative and
quantitative analysis of drugs. 90

 

 

 

 

 

 

 

 

 

x

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