Department of Pharmacy

An Assignment On

NIR Spectroscopy as a PAT Tool in the Tablet Manufacture

Process

Course Title: Pharmaceutical Quality Assurance and

Validation
Course Code: PHARM-4103

Submitted By: Submitted To:

Roll No: 1930027 Rehnuma Tanjin
Reg. No: 2209 Lecturer
Session: 2019-2020 Department of Pharmacy
Department of Phamacy Islamic University, Kushtia-7003
Islamic University, Kushtia-7003
Introduction

Near Infrared (NIR) spectroscopy is a secondary analytical technique used for rapid evaluation
and identification of chemical and physical properties of substances. It utilizes near-infrared light
to gather information about a sample's composition and characteristics. NIR spectroscopy utilizes
the portion of the electromagnetic spectrum ranging from approximately 780 to 2500 nanometers
(nm), which lies adjacent to the visible light region.

The fundamental principle behind NIR spectroscopy is based on the fact that different chemical
compounds absorb and scatter light in the NIR region in a characteristic manner. This interaction
is influenced by the presence of specific molecular bonds, functional groups, and molecular
arrangements within the sample. By analyzing the absorption and scattering patterns of NIR light,
it is possible to identify and quantify various chemical constituents in a sample. [1]

Process Analytical Technology (PAT) is a system for monitoring and controlling pharmaceutical
manufacturing processes in real time. It's a voluntary framework that helps pharmaceutical
manufacturers improve the quality and efficiency of their products.

What does PAT do?

Measures Critical Process Parameters (CPPs): PAT measures CPPs, which are factors that
affect Critical Quality Attributes (CQAs).
Monitors CPPs: PAT monitors CPPs to ensure they stay within defined limits.

Analyzes raw materials, in-process materials, and final products: PAT uses in-line or on-line
instrumentation to analyze these materials.

How does PAT work?

• PAT uses spectroscopic techniques, such as infrared (IR), Raman, and UV-Vis
spectroscopy.
• PAT uses chromatographic techniques.
• PAT uses particle size and mass measurement tools.
• PAT uses advanced data analysis strategies, such as machine learning and chemometric
tools.

The FDA’s Process Analytical Technology (PAT) initiative, “Pharmaceutical cGMPs for the 21st
Century – A Risk-Based Approach,” has driven the development of advanced analytical tools.
Among these, near-infrared (NIR) spectroscopy stands out as a key technology for improving
product development and manufacturing efficiency.

NIR spectroscopy can be applied at multiple stages of tablet manufacturing, including raw material
identification, blend uniformity, and critical process steps like granulation, drying, and tablet
characterization. Its versatility and ease of use make it one of the most practical PAT tools
available today. [1,2]
This non-destructive technique allows for the measurement of tablet properties such as drug
content, hardness, and dissolution from a single test. It has become a widely accepted industry
standard, though unlike HPLC, there is no universal protocol for developing calibration models.
Each implementation requires customized sample selection and model-building techniques.
Recent advancements in NIR instruments, data modeling, and sample selection have improved
accuracy and reliability, making it an essential tool in modern pharmaceutical manufacturing. This
review explores the fundamentals of NIR spectroscopy and its applications in tablet production.

Fundamentals of NIR Spectroscopy

Basic Mechanism of Near-Infrared Spectroscopy (NIRS)

NIR spectroscopy is based on the Beer-Lambert Law, which states that the amount of light
absorbed by a substance depends on its concentration. The higher the concentration, the more light
it absorbs.

Unlike UV-Vis spectroscopy, which measures how light excites electrons, NIRS interacts with
entire molecules. Instead of exciting electrons, near-infrared radiation causes molecules to vibrate
in different ways, such as stretching, bending, and rocking. This is why NIRS is also called
vibrational absorption spectroscopy.

Each molecule has unique vibrational modes depending on its chemical structure. For example, a
water molecule vibrates in specific ways when exposed to infrared light:

o Asymmetric stretch – one hydrogen bond shrinks while the other extends.
o Symmetric stretch – both hydrogen bonds shrink or stretch together.
o Scissoring bend – hydrogen atoms move toward each other like a pair of scissors.

By analyzing how molecules absorb near-infrared light and their specific vibrational patterns, NIR
spectroscopy can identify chemical compositions and properties of substances accurately.

Basic principle of NIR Spectroscopy

NIR identification principle is based on the reason that a material will absorb NIR energy and will
transmits or reflects it in a unique pattern according to the physical and chemical characteristics.
Hence we can use NIR for both qualitative and quantitative analysis. The in the electromagnetic
spectrum NIR region is located at the wavelength range between 780 and 2565 nm and wave
number range 12820-3959 cm-1, hence it covers the wavelength range adjacent to the mid infrared,
which may extend to the visible region.(3)

The sample is irradiated with NIR light source. This light is then absorbed by molecules only
when there is change in dipole moment because of molecular vibrations. O-H, N-H, S-H and R-
H groups have a high dipole moment hence they show strong NIR absorbance. On other case
some diatomic molecules like H2, O2, N2 do not absorb NIR radiation as there is no change in
dipole moment due to molecular vibrations.(3)

Types of NIR spectrophotometers

NIR spectrophotometers can be classified in two types based on the wavelength selection system
as dispersive and non-dispersive instruments.

1. Dispersive instruments which are the most commonly used wavelength selection systems are
the monochromators.
2. Non-dispersive instruments, here the variety of selection systems is broad. Different selection
devices such as conventional filters, Fourier transform (FT)-NIR type and AOTFS (Acusto
Optic Tunable Filters) are used. The chosen wavelengths will use radio-frequency signals
will alter the refractive index of a crystal usually TeO2and hence it transmits light of any
given wavelength or performs a wavelength scan much more rapidly. (5)

Uses

NIR spectroscopy is used in the pharmaceutical industry before the PAT initiative was introduced
in the early 2000s, but its use was limited to a few identification and the quantitative analyses of
raw materials. NIR instruments were being adopted by larger multinational companies in the late
1990s for raw- material identification in order to reduce the cost of laboratory testing and also
provide assurance that all materials delivered are correctly labeled. NIR technology also offers the
means for 100% inspection. (6)

Advantages of NIR

1. NIR Spectroscopy is a flexible and versatile technique compared to other methods. Depending
on characteristics of samples and analytical conditions broad variety of devices can be
incorporated.
2. Due to the advent of bright light sources, fiber optics and sensitive detectors, NIR optical paths
for liquid samples is in mm or even cm rather than microns hence difficult sampling techniques
of IR is solved by NIR.
3. As NIR radiation has much greater penetration depth into the sample hence there is no need of
sample dilution.
4. Because of that it minimizes sample preparation errors and sample destruction.(7)

Disadvantages of NIR

1. NIR spectra is broad, has overlapping peaks as compared to IR spectra.

2. Structural elucidation of wetted samples is not possible as water bands are too strong.(7)

Role of NIR in tablet manufacturing

At-Line Testing of Excipients: When a drug product is manufactured, the first priority is to
identify correct API, correct material and also correct grade of pharmaceutical excipients. NIR is
sensitive to physical as well as chemical parameter; hence it can be employed as an excellent
technique for such identification. (8)

Raw Material Identification and Verification:

• Rapid screening: NIR can quickly identify and verify incoming raw materials (active
pharmaceutical ingredients (APIs) and excipients) by comparing their spectral fingerprint
to a reference database, ensuring correct material usage and preventing mix-ups.

• Purity assessment: By analyzing specific NIR absorption bands, potential impurities or

variations in raw materials can be detected.

Blending Operations: Next stage in manufacture of dosage form blending of API with excipients
in order to a homogeneous blend. Here there is blending of non-cohesive powders will be
considered. Usually a vessel is charged with the components of formulation and is mixed for a
given period time. At end the vessel is sampled for analysis by HPLC in order to homogeneity and
potency of API within a formulation. This approach does not take into account any quality
measurements, by using any on-line approach to measurement by NIR hence greater understanding
of the blending process is achieved.

• In-process monitoring: NIR probes can be integrated into blending equipment to

continuously monitor the distribution of API within the powder blend, ensuring consistent
drug loading throughout the batch.

• Sampling analysis: NIR can be used to analyze representative samples from different parts
of the blend to identify potential inconsistencies in drug distribution.
Moisture Content Analysis:

• Non-destructive measurement: NIR readily detects water content in powders and granules,
enabling real-time monitoring of moisture levels during granulation and drying processes,
optimizing the formulation.

• Process control: By tracking moisture levels, adjustments can be made to drying parameters
to maintain desired moisture content in the final tablet.

Tablet Coating Uniformity:

• Film thickness monitoring: NIR can analyze the coating thickness of tablets by measuring
the absorption of NIR light through the coating layer, ensuring consistent coating application.

• Identifying coating defects: Variations in coating composition or thickness can be detected

through NIR analysis, allowing for timely adjustments to the coating process.

Real-time Monitoring and Feedback Control:

• Process Analytical Technology (PAT): Integrating NIR spectroscopy with manufacturing

equipment enables real-time data collection, enabling immediate feedback and adjustments to
process parameters to maintain product quality.

• Statistical Process Control (SPC): NIR data can be used for real-time SPC analysis,
identifying potential deviations from desired product specifications and triggering corrective
actions.

Key benefits of NIR spectroscopy in tablet manufacturing:

• Real-time monitoring: NIR can be used inline or at-line to provide immediate feedback on
tablet properties during manufacturing, enabling adjustments to process parameters as needed
to maintain desired quality.

• Non-destructive analysis: Unlike some traditional methods, NIR analysis does not damage
tablets, allowing for testing of a larger sample size without affecting the product.

• Multi-component analysis: NIR can simultaneously measure multiple tablet attributes like
drug content, excipient composition, and moisture content in a single measurement.
• Rapid analysis: NIR provides quick results, enabling faster quality checks and reduced
production downtime.

• Process Analytical Technology (PAT) compliance: NIR is a valuable tool for implementing
PAT strategies, allowing for real-time monitoring and control of the manufacturing process.

• Reduced waste: By identifying potential quality issues early on, NIR can help minimize the
need to discard defective tablets, improving production efficiency.

Specific applications of NIR in tablet manufacturing:

• Blend uniformity check: Analyzing the uniformity of blended powders before compression
to ensure consistent drug distribution.

• Tablet hardness monitoring: Assessing tablet hardness to ensure proper disintegration and
dissolution.

• Drug content analysis: Quantifying the active pharmaceutical ingredient (API) content in
tablets.

• Moisture content measurement: Monitoring moisture levels in tablets to prevent issues with
stability and dissolution.

• Coating thickness verification: Analyzing the thickness of film coatings on tablet.

Near-infrared (NIR) spectroscopy offers significant benefits as a Process Analytical Technology

(PAT) tool due to its non-destructive nature, ability for real-time monitoring, and cost-
effectiveness, allowing for rapid analysis of samples without altering their integrity, providing
continuous insights into a process, and generally having lower operational costs compared to other
analytical methods.

Key benefits of using NIR as a PAT tool:

• Non-destructive analysis: NIR radiation does not significantly damage samples, enabling
analysis of raw materials, intermediates, and final products without compromising their
integrity, which is crucial in quality control and research applications.

• Real-time monitoring: NIR instruments can be integrated directly into production lines to
provide continuous data on key process parameters, allowing for immediate adjustments and
proactive quality control.
• Rapid analysis: NIR measurements are typically very fast, providing results within seconds
or minutes, enabling quick decision-making and faster process optimization.

• Minimal sample preparation: In many cases, NIR analysis can be performed on samples
directly, without the need for extensive sample preparation, which saves time and resources.

• Versatility: NIR spectroscopy can analyze a wide range of materials, including liquids, solids,
and semi-solids, making it applicable across diverse industries like pharmaceuticals, food,
chemicals, and agriculture.

• Cost-effectiveness: While initial setup costs for NIR systems can be substantial, the rapid
analysis and minimal sample preparation can lead to lower operational costs over time.

Specific applications of NIR in PAT:

• Process monitoring: Tracking key parameters like concentration, moisture content, and
composition during production runs to identify potential issues early.

• Quality control: Analyzing finished products to ensure they meet quality standards before
release.

• Batch release testing: Rapidly analyzing samples to expedite product release.

• Process optimization: Identifying critical process parameters and adjusting process

conditions to improve product quality and consistency.

Important considerations when using NIR:

• Calibration development: Accurate NIR analysis requires careful calibration development

using representative samples to ensure reliable results.

• Spectral interpretation: NIR spectra can be complex, requiring specialized software and
expertise for accurate data analysis.

• Matrix effects: The composition of the sample matrix can influence NIR spectra, necessitating
careful consideration of potential interferences.

Limitation of using NIR as a PAT tool

While NIR spectroscopy is a valuable PAT tool in tablet manufacturing, its limitations
include: low sensitivity to certain components, potential interference from excipients, difficulty in
detecting low concentrations of active pharmaceutical ingredients (APIs), dependence on robust
calibration models, susceptibility to sample variability, and challenges in monitoring complex
blend uniformity in continuous manufacturing processes; requiring careful consideration when
implementing it for real-time quality control.

• Limited sensitivity: NIR primarily detects vibrational overtones of functional groups, which
can lead to low sensitivity for certain components, particularly when present in low
concentrations.

• Interference from excipients: The spectra of excipients can sometimes overlap with the API
signals, making it difficult to accurately quantify the API content.

• Calibration dependence: Accurate NIR analysis relies heavily on robust calibration models,
which require a large and diverse set of reference samples to account for potential variability
in raw materials and manufacturing processes.

• Sample variability: Factors like particle size distribution, moisture content, and powder flow
characteristics can affect NIR readings, requiring careful sample preparation and monitoring
for consistency.

• Depth penetration limitations: NIR radiation only penetrates a shallow layer of the sample,
potentially leading to inaccurate results if the sample is not uniformly mixed throughout.

• Challenges in continuous manufacturing: Monitoring blend uniformity in a continuous

process can be complex.

Important considerations when using NIR in tablet manufacturing:

• Targeted applications: NIR is most effective for monitoring bulk properties like moisture
content, blend uniformity of major excipients, and detecting significant changes in formulation
composition.

• Validation and qualification: Thorough validation and qualification procedures are necessary
to ensure the accuracy and reliability of NIR measurements.

Future Perspective & Conclusion

The future of NIR technology is poised for significant advancements, primarily through
its integration with artificial intelligence (AI) and machine learning (ML), enabling enhanced
process control and real-time data analysis across various industries, particularly in Process
Analytical Technology (PAT) applications, leading to more precise monitoring and optimization
of manufacturing processes.

As the pharmaceutical industry transitions toward continuous manufacturing, NIR spectroscopy

will play a crucial role in optimizing processes, reducing costs, and ensuring product quality.

In conclusion, NIR spectroscopy offers a transformative approach to tablet manufacturing by

enabling real-time, non-destructive analysis across multiple process stages. Despite
implementation challenges, its benefits in quality assurance, efficiency, and regulatory compliance
make it a vital component of modern pharmaceutical manufacturing strategies.

References:

1. Gabriele R, Near-infrared spectroscopy and imaging: Basic principles and pharmaceutical

applications, Advanced Drug Delivery Reviews, Volume 57, 2005, Page No. 1109–1143.
2. Hailey A, The Role of NIR Spectroscopy in the Measurement of Pharmaceutical Manufacture,
Pfizer Central Research, Volume 25, 2014, Page No.9-10
3. Franklin EB, Theory and principles of near infrared spectroscopy, Spectroscopy Europe,
Volume 14, 2002, Page No.12-18
4. Dr. Marcel B, Use of NIR spectroscopy and multivariate process spectra calibration for
pharmaceutical solid samples analysis, Journal of pharmaceutics, Volume 1, 2013, Page No.56-
64.
5. http://guidedwave.com/_img/userfiles/file/appnotes/NIRS pectProcessAnalysisO.pdf Received
on: 15-12-2010.
6. Brad S, The current state of near infrared spectroscopy application in the pharmaceutical
industry, Journal of near infrared Spectroscopy, Volume 22, 2014, Page No.153 156.
7. http://www.aapspharmaceutica.com/inside/discussion_groups/social/imagespdfs/ Received on:
15-12-2010.
8. Sanchez FC, Massart DL, Dive SS and Hailey PA, The role of NIR spectroscopy in the
measurement of pharmaceutical manufacture, Fresnius Journal of Analysis chemistry, Volume
352, 1995, Page No.771-778.