Measurement Techniques for Formulated Products. Pharmaceutical tablets, liquid detergents used in laundry and paints

Contents

1.0 Introduction

2.0 Paints
2.1 Particle Size Analysis of Pigments using Laser Diffraction
2.2 Other measuring techniques
2.2.1 X-ray Powdered Diffraction (XRD)
2.2.2 Mass spectrometry
2.2.3 Polarisation Intensity Differential Scattering (PID)

3.0 Pharmaceutical tablets
3.1 Raman Spectroscopy for Pharmaceutical Drugs
3.2 Other techniques
3.2.1 Raman Imaging Microscope for tablets
3.2.2 X-ray computed tomography density measurement in tablets
3.2.3 Near-Infrared chemical imaging for tablet

4.0 Laundry Detergent
4.1 Scanning Electron Microscopy (SEM) for detergent granules
4.2 Other Techniques
4.2.1 Energy Dispersive X-Ray Spectroscopy EDX
4.2.2 Fourier transform infrared microscopy
4.2.3 Atomic force microscopy

5.0 References

1.0 Introduction

In defining "formulation," one may consider it as the blending of a different compound that is not-reactionary among themselves to ultimately get a combination that bears some specific characteristics (Conte et al, 2011, pg.88). Its key importance is the assembling of different components in suitable structures and relationships based on a certain combination formula. A combination of these compounds is made based on a products' standard.

Various products are considered to be made out of a combination of various elements. These products include; paints, food, medicinal tablets, and liquid detergents among others. These products are made out of a combination of various products in a certain proportion that is considered in the formulation. Product designs, therefore, focus much on the results of the combination of various materials. In this case, the formulation is developed systematically under the following five-step:

- Stipulate the end quality that is to be obtained.
- Identify data required to gather the composition of raw materials, the cost, and the qualities.
- Determine the processing variables to be used including the raw materials limits.
- Identify the methodology to use including; experimental design, linear programming, and quantitative techniques.
- Profile the products and consider conducting a test to determine their validity that would help formulation achieve the required quality.

This paper will seek to discuss various products that have been formulated. Various techniques will be discussed for each formulated product. The products in consideration, therefore, will include; pharmaceutical tablets, liquid detergents used in laundry and paints.

2.0 Paints

In the acquisition of decoration, protection against environmental factors as well as prolonged life of synthetic and natural materials, paints are very important and crucial.

Paints can be categorised into two: decorative paints which are used in decorating site as well as protecting certain objects and buildings. The other category is the industrial coating that is used on manufactured goods such as cars.

The constituents of paint

Paints have elements that include:

- Pigments - which are used in imparting opacity and colour.
- The resin which is a polymer. Resin bears some matrix that helps in holding the pigments in position.
- Extenders - these are pigments that have large particles that are added to help in the improvement of the paint by strengthening the save binder and film as well as adhesion.
- Solvent or thinner - This is fluid that is used in the reduction of the paint's viscosity so that it can be applied better. There are types of paints that are referred to as water-borne. These types of paints are said to be replacing paints that use organic compounds that are volatile. These compounds are considered very harmful to the atmosphere.
- Additives - Additives are used in the modification of dry film or liquid paint's properties.

In regard to different types of paints, additives can be said to include:

- Silicones that are used for resisting weather.
- Driers that are used in the acceleration of the time of paint drying.
- Dispersants that are used to stabilise and separate the particles of pigments.
- Anti- settling agents that used in the prevention of the settling of pigments.
- Thixotropic agents that are used produces a jelly-like feature out of a paint that helps in the break- down of a paint to the fluid when the brush is dipped in the paint or stirred.
- Algaecides and fungicides are used in the protection of paint films that are exterior against contracting moulds, lichen, and algae or becoming disfigured.
- Bactericides are used in the preservation of the water based paints within a can.

Paints are usually moulded based on their anticipated use -groundwork, undercoat, uncommon completions (matt, gleam, heat resistance, abrasion resistance, anti- corrosion). Pigment powder is separated into individual particles which are covered by and scattered in the fastener - referred to as "wetting out". Dissolvable or solvents are later added in order to attain a certain consistency. Every bunch of the requirements is altogether blended in vast, containers that are stirred with the required added substances (Figurel). Sums extending up to 40 000 dm3 of paint might be made in a solitary cluster.

Coating and painting are heterogeneous items comprising of shades, pitches, added substances among others, and are very complex in nature. Many smooth, profoundly specular coatings, for example, car paints and machine coatings, are subjected to impressive execution requests and makers spend huge totals every year on screening and repair covering surface quality. Moreover, changing item determinations and natural controls will keep on affecting the preparing parameters that impact surface appearance and quality. Along these lines, it is key to create powerful strategies to screen surface quality. A full portrayal of undefined or nanostructured types of coatings at the micro-structural level has some characteristic troubles related with the absence of long range request and reference mixes, which regularly make their review troublesome. Just by the blend of various portrayal methods, it is conceivable much of the time to accomplish profitable compound and auxiliary data.

2.1 Particle Size Analysis of Pigments using Laser Diffraction

Paints include various element, and the characteristics of these elements have a significant impact on the final product. Paints contain roughly 40% of Pigments and extenders, measurement of their particle size serves as an excellent predictor of the final product quality, therefore, it is considered to be a critical parameter in paints that affects surface finish. In order to reduce the problems related to paints quality, it is important to characterise the pigment sample at the microscopic level as it is an important element to providing good quality paints. Rheological behaviour such as viscosity, flow rate thixotropic behaviour or adhesion is also affected by the particle size distribution. (Debnath and Vaidya, 2006)

Various paint pigments work by selectively absorbing and reflecting a certain wavelength of light (figure 2) (Particle, 2008). The ability of a paints pigment to absorb a certain wavelength of light increases by reducing the particle size, until when the particles reach a point where it becomes translucent to the incident light. This factor makes the measurement of pigment particle size extremely important to it performance. (Application Information, 2014).

Figure 2: Pigments absorbing and reflecting certain wavelength of light. (Particle, 2008)

For a comprehensive pigment characterization, there are a number of analytical techniques which includes FT-IR, SEM/TEM, EDX, XRD and laser diffraction to establish shape/particle size, functional group and particle size distribution etc. (Debnath and Vaidya, 2006). Various different particle sizing technologies are being currently used to measure the particle size distributions of pigments but, LASER DIFFRACTION is considered to be the most common technique for determining the particle size distribution of liquid media of low viscosity such as paints. It enables comparison of the effectiveness of dispersion techniques (McGarvey, McGregor and McKay, 1997), mainly due to its ease of use and the varied ways that sample can be presented for analysis. (Application Information, 2014).

Laser Diffraction

Laser diffraction has become one of the most widely used techniques for particle size analysis in the coatings/paints industry, with applications from product development through to production and quality control. It relies on the fact that particles passing through a laser beam will scatter light at an angle that is directly related to their size. As particle size decreases, the observed scattering angle increases logarithmically. Scattering intensity is also dependent on particle size, diminishing with particle volume. Large particles therefore scatter light at narrow angles with high intensity, whereas small particles scatter at wider angles but with low intensity, as shown in figure 3. It is this behavior that instruments based on the technique of laser diffraction exploit in order to determine particle size. (Diffraction, 2017}

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Figure 3: Scattering of particle vs intensity (Application Information, 2014)

The basic principle of Laser Diffraction is shown in figure 4. A stream of pigments particles contained in a sample flow cell, where a beam of collimated and monochromatic light from a low power neon-helium laser (wavelength - 633nm) passes at a controlled rate (McGarvey, McGregor and McKay, 1997). Low power neon-helium laser is scattered by the pigments and passes through a Fourier Lens to form a diffraction pattern of concentric rings at the focal plane of the lens. Even though the particle/pigments are moving the diffraction pattern is tends to be stationary. At the focal plane, a special array of detectors collects the scattered light from an assembly of solid particles over a range of angles. The scattering angle is inversely proportional to the particle size, therefore, the scattered light by the smallest particle falls on the outermost detectors.

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Figure 4: basic principle of Laser Diffraction (Application Information, 2014)

The unscattered laser usually falls on the centremost of the detector through the small aperture, the intensity of the unscattered light can be used to measure the volume concentration of the pigments (McGarvey, McGregor and McKay, 1997).

As can be seen in figure 4, typical Laser diffraction system consists of a Laser which is to provide coherent light of fixed wavelength, detectors to measure the scattered light over a range of angles and sample flow cell to make sure the material passes through the beam. The wavelength of the beam is very important as smaller wavelength can improve sensitivity to sub-micron particles.

In laser diffraction, particle size distributions are calculated by comparing a sample's scattering pattern with an appropriate optical model. Mie Theory provides a rigorous solution for the calculation of particle size distributions from light scattering data. It predicts scattering intensities for all particles, small or large, transparent or opaque. Mie Theory allows for primary scattering from the surface of the particle, with the intensity predicted by the refractive index difference between the particle and the dispersion medium. It also predicts the secondary scattering caused by light refraction within the particle - this is especially important for particles below 50 microns in diameter, as stated in the international standard for laser diffraction measurements. (Diffraction 2017)

The Advantages of Laser Diffraction

Laser diffraction is considered to be a non-destructive technique which can be used for powders and dispersions. Particle size is derived using fundamental scientific principles and it is easy to use, fast and have a wide dynamic range. Further advantages are:

- A wide dynamic measuring range - this technique can measure paint pigments in the range from (0.01 micron to mm) without replacing the optical configuration, also make sure that the particles are well-dispersed and detect the agglomerated particles.
- Flexibility - this technique is well suited for spray paints, emulsions, dry powders and suspensions.
- Rapid data acquisition
- Can produce volume-based particle size distribution - this tells where most of the mass of material is located.
- High repeatability- data can be attained rapidly.

The Disadvantages of Laser Diffraction

There are few drawbacks related to laser diffraction, as the majority of paints pigments are in sub-micron range, laser diffraction instrument normally struggles to provide accurate data as particle size below lu.m scatter light weakly and without any maxima and minima, the instrument encounter difficulties in the measurement with weak scattering signals. Few other drawbacks are - inaccuracy of measurements for non-spherical particles and the result usually vary significantly with optical parameters. (Richard N. Kelly, 2004)

Particle size analysis of pigments

The paint pigment particles are normally milled to makesurethatthey are well below the size required by the desired type of finish. Measurement of the PSD down to much finer sizes can allow the optimisation of paint formulation and manufacturing process (Particle, 2008).

For most application requirement for the pigment particle size are very small (roughly 200nm or less] and the pigment dispersion must neither agglomerate nor settle during storage as it can affect the rheological behaviour such as viscosity, flow rate thixotropic behaviour or adhesion, Therefore, the pigment particle should be milled to reduce the particle size and break up any strongly bound aggregates. To ensure optimal milling it is very important to monitor size during the milling process. (Diffraction, 2017)

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Figure 5: Particle size distribution of yellow pigment in the milling process. (McGarvey, McGregor and McKay,

The f gure 5 shows the data produced using Laser Diffraction to analyse yellow pigment removed at regular intervals during a milling process. Its shows that the relativity broad particle size distribution of pre-mix is reduced to a narrow particle size distribution mainly due to the breakup of agglomerated particles, followed by as more gradual reduction produced by the breakup of larger primary particles. [Diffraction, 2017}. Below the figure 6 shows various different milling process to reduce the pigment particle size.

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Figure 6: Influence of various milling on pigment particle size. (McGarvey, McGregor and McKay, 1997)

Paints include various element, and the characteristics of these elements have a significant impact on the final product. Paints contain roughly 40% of Pigments and extenders, measurement of their particle size serves as an excellent predictor of the final product quality, therefore, it is considered to be a critical parameter in paints that affects surface finish. In order to reduce the problems related to paints quality, it is important to characterise the pigment sample at the microscopic level as it is an important element to providing good quality paints. Rheological behaviour such as viscosity, flow rate thixotropic behaviour or adhesion is also affected by the particle size distribution. (Debnath and Vaidya, 2006)

2.2 Other measuring techniques

2.2.1 X-ray Powdered Diffraction (XRD)

X-ray diffraction (XRD) is an analytical technique commonly used for phase identification and characterisation of a crystalline material such as pigments in paints based upon their diffraction pattern.

XRD is based on constructive and destructive interference of monochromatic X-rays and pigment sample (Crystalline). Cathode ray tube commonly generates X-rays, which are filtered to produce monochromatic radiation, collimated to concentrate and finally the radiation is directed toward the pigment/sample. The interaction of an incident beam of monochromatic X-rays with the crystalline material leads to constructive interference (this is the process of diffraction) which is described by Bragg's Law (n\=2d s\n 6). The direction of diffractions depends on shape and size of the crystalline material. The schematic of XRD is shown in the figure below (Techniques, 2017).

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Figure 7: Schematic of XRD

The Bragg's Law (n\=2d sin 6) relates the wavelength of the X-ray to the diffraction angle and the lattice spacing in the paints pigments, these diffracted X-rays are then detected, processed and counted which is then output to a device such as a printer or computer monitor. By scanning the sample through a range of 29angles, all possible diffraction directions of the lattice should be attained due to the random orientation of the powdered material. Conversion of the diffraction peaks to d-spacings allows identification of the mineral because each mineral has a set of unique d-spacings. Typically, this is achieved by comparison of d-spacings with standard reference patterns (Techniques, 2017).

As mentioned above, XRD is commonly used for the identification of unknown materials such as inorganic compounds. In the paint industry, XRD technique establishes the crystal phase and chemical identity of a number of very important pigments which are commonly used in various refinish paints, automotive and decorative. The important pigments include copper phthalocyanine blue, viz. titanium dioxide, scarlet chrome etc. since most of these pigments used in paints are crystalline materials and exist in different polymorphic form, it is very important to make sure not only the chemical purity but also the crystalline purity of the pigments for quality improvement. Below the figure shows the relative amounts of anatase and rutile in titanium dioxide, which is commonly used in the paint industry and these identities of various pigments are normally used by quality control department for analysing pigments in finished product and for rapid screening of incoming material from the different source. (Debnath and Vaidya, 2006)

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Figure 9: XRD pattern of titanium dioxide (anatase) and (rutile). (Debnath and Vaidya, 2006)

The analysis of titanium dioxide in paints is very important because of the inherent importance of this pigment for hiding power and because, with the exception of the resin, it is the most costly ingredient in typical paint formulations. (Kamarchik and Cunningham, 1980)

In the paint industry, various different grades of pigments and extenders are used for different functional requirements and they commonly vary widely from natural minerals to synthetics, metallic to organic, depending on the source of raw material the pigments and extenders leave enough scope for variation in chemical purity.

When the extenders and pigments are obtained from different sources, changes in the paint performance are observed mainly due to the physicochemical characteristics of the pigment particles. To reduce this problem, it is extremely vital to characterise the pigments at the microscopic level to control the paint quality. Therefore, the quality control department uses the XRD patterns for analysing pigments in finished paint and for rapid screening of incoming material from the different sources. (Debnath and Vaidya, 2006)

2.2.2 Mass spectrometry

Mass spectrometry is a technique of analysis which is mostly implemented in measuring the mass-to-charge ratio of a single molecule out of many presents in a sample. At times this technique is beneficial in calculating the exact molecular weight of a sample component. Therefore, mass spectrometry technique is a basically a method that can be used to find out the unknown compounds, to find out the structure as well as chemical properties of molecules and finally to quantify the known compounds. This is typically done using a mass spectrometer equipment. The equipment comprises of three main components, which are; ionisation source, mass analyser and ion detection system.

The ionisation source: into gas-phase ions, the molecules are converted in order to move them about and similarly manipulate them by external electric and magnetic fields. In order to perform this, a Nanoelectrospray ionisation may be used. The technique helps to create negative and positive charged ions.

The mass analyser: immediately the molecules are ionised, then according to mass-to-charge ratios, the ions are separated. There are various types of mass analysers which are available and each of them have trade-offs according to the resolution of separation, the speed of operation and operational requirements.

Ion detection system: once the ions are separated, they are measured and then taken to a data system. In the data system, the storage of m/z ratios together along with their relative abundance is done. Then using the m/z ratios available in the sample versus the intensities, a mass spectrum can be plotted. An example is shown below;

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Figure 10: an example of a mass spectrum (Brown & Garang', 2013).

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Figure 11: a schematic diagram showing a mass spectrometry technique (Brown & Garang', 2013)

Advantage

- This technique requires small sample size and it is fast
- Mass spectrometry differentiates isotopes
- The technique can run mixtures when combined with GC and LC. Disadvantages
- It is not easy to use with non-volatile compounds
- The technique does not provide structural information directly.

From the scientific overview, this technique is used in identifying major categories in coatings. To identify the more volatile solvents components, Mass Spectrometry is very critical. Those that cannot be affected by the Mass Spectrometry are usually introduced into the source of ion directly. The analysis is then conducted to identify a target class of compounds. Soft ionisation method is used to synthesise low- volatility functionalized group of monomers. The Mass Spectrometry identify that the polymers with high molecular weights can be fragmented of degraded when subjected to high temperatures. Mass Spectrometry is able to help in identifying characterization with fewer volatility constraints.

To study the modern paint materials, mass spectrometry technique is frequently applied combined with Gas Chromatography (GC). GC-MS provides information on additives, pigments, dyes, solvents and polymers. This technique is considered to be the fastest method for the identification of organic pigments. The technique can also be used to fully characterise the paint formulation which includes binders, additives, pigments, filler and etc. Below the figure shows the mass spectrum of Dupli paint formulation with all the identified compounds. This technique also reveals the minor and trace binders which are difficult to determine with other characterization technique.

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Figure 12: GC-MS trace of the alkyd resin paint. (Germinario, van der Werf and Sabbatini, 2016)

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Figure 13: GC-MS products identified in the Paint. (Germinario, van der Werf and Sabbatini, 2016)

In the paint industry, various different grades of additives, pigments, dyes, solvents and polymers are used for different functional requirements and they commonly vary widely from natural minerals to synthetics, metallic to organic, depending on the source of raw material the end product leave enough scope for variation in chemical purity. (Germinario, van der Werf and Sabbatini, 2016)

When paint elements are obtained from different sources, changes in the paint performance are observed mainly due to the physicochemical characteristics of the paint particles. To reduce this problem, it is extremely important to characterise the paint formulation at the microscopic level to control the paint quality. Therefore, the quality control department normally uses GC-MS technique for analysing the paint formulation in finished paints for chemical purity to ensure the final product doesn't contain any impure substance as this can affect the paint quality. Therefore, GC-MS technique is used to trace any impure substance which can affect the performance. (Debnath and Vaidya, 2006)

2.2.3 Polarisation Intensity Differential Scattering (PID)

Almost all the laser-based technique makes no allowance for the shape of the paint pigment under test, the main reason for this is the underlying assumption which is used for calculating the particle size distribution. All the laser techniques are based on spherical system and the result usually varies significantly with optical parameters. Also, the majority of paints pigments are in sub-micron range, laser diffraction instrument normally struggles to provide accurate data as particle size below lu.m scatter light weakly and without any maxima and minima, the instrument encounter difficulties in the measurement with weak scattering signals. Therefore, many paint industry utilises PIDS system to size sub-micron and nonspherical particles. (BECKMAN COULTER, 2005)

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Figure 14: Scattering from different polarisation.

PIDS technology is simple and takes advantage of the well-established and understood Mie theory of light scattering. PIDS relies upon the transverse nature of light, i.e., it consists of a magnetic vector and an electric vector at 90 degrees to it. If, for example, the electric vector is "up and down" the light is said to be vertically polarised. When illuminating a sample with a light of a given polarised wavelength, the oscillating electric field establishes a dipole, or oscillation, of the electrons in the sample. These oscillations will be in the same plane of polarisation as the propagated light source. The oscillating dipoles in the particles radiate light in all directions except that of the irradiating light source. (BECKMAN COULTER, 2005)

PIDS takes advantage of this phenomenon. Three wavelengths {450 nm, 600 nm, and 900 nm) sequentially illuminate the sample, first with vertically and then horizontally polarised light. We measure the scattered or radiated light from the samples over a range of angles. By analysing the differences between the horizontally and the vertically scattered light for each wavelength we gain information about the particle size distribution of the sample. (BECKMAN COULTER, 2005)

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Figure 15: Pigments particle size distribution by PID - Dotted line: d = 150 nm; dashed line: d = 100 nm; and solid line: d = 50 nm

The above figure shows the angular patterns of 50nm particles and lOOnm particles are recognisable and this is also verified through experimentation and theoretical simulation, this illustrates that accurate sizing of smaller particles are difficult without the use of PIDS techniques.

Paints include various element, and the characteristics of these elements have a significant impact on the final product. Paints contain roughly 40% of Pigments and extenders, measurement of their particle size serves as an excellent predictor of the final product quality, therefore, it is considered to be a critical parameter in paints that affects surface finish. Since most of the commercial pigments are available in sub-micron range they are difficult to measure using laser based technique. Therefore, many companies characterise their particle using PIDS technology.

In order to reduce the problems related to paints quality, it is very important to characterise the pigment sample at the microscopic level as it is an important element to providing good quality paints. Rheological behaviour such as viscosity, flow rate thixotropic behaviour or adhesion is also affected by the particle size distribution. (Debnath and Vaidya, 2006)

3.0 Pharmaceutical tablets

Pharmaceutical tablets are strong dosages that are solid in nature which comprises of at least one dynamic excipients' ingredient. Excipients are a critical piece of the formulation of the tablet. Excipients are considered pharmacologically dormant elements incorporated into the detailing of the formulation which is utilised as a dynamic ingredients carrier. Traditionally, excipients were used as tablets formulation that incorporated;

1. Lubricants
2. Disintegrants
3. Diluents/fillers
4. Glidants
5. Binders
6. Miscellaneous

Diluents: The diluents are utilised to build the mass substance of the content of any dosage. This is facilitated in cases where the dynamic constituent to be joined in the components of formulation has less amount. For instance, if the dynamic fixing is only 5 milligrams, a tablet of only 5 mg, in that case, is extremely hard to fabricate and handle as well, subsequently, the mass substance is expanded by expansion of inert excipient (Johan & Bramwel, 2016).

Binders: Binders or fasteners are considered as fluids or dry powders being added amid wet granulation to help in the elevation of granules that in the promotion of the granules or in the promotion of the compactness of the granules compact amid direct pressure. Binders, therefore, help in enhancing the mechanical quality of the tablets. It provides mechanical strength to the tablet. Fasteners can be in the form of fluid of powder. These are;

Powder binders: These include the methylcellulose, cellulose, PEG and polyvinyl pyrrolidine.

Fluid binders: Starch, Sucrose, PEG, HPMC, PVP, and gelatin.

Fasteners in the formulation can be added as follows;

- To make the faster be distributed evenly, the fastener can be added in powder form before agglomerated in liquid to make it wet.
- The fluid fastener is formed as the solution is produced from the wet granulation.
- Dry powder is mixed with other elements then compacted to form tablets of slugs.

Disintegrant: As the dosage is broken into tiny elements, the formulation has added some disintegration. The tiny elements developed to produce greater surface area that increases drug dissolution. A number of propositions have been put forward in regard to the disintegration mechanisms.

- By breaking into fragments: Upon coming to close contact with the fluid, tablets break into small elements since the fluid enters in their pores. Hydrophilic polymers are however added into the formulation which helps in water uptakes of the tablets to improve.
- By swelling: rupture after swelling of the tablets takes place after the tablets come into close contacts with water. The tablets hence break into very tiny pieces.

Some of the example so disintegrants include; alginates, cellulose, PVP, clay, starch derivatives, and starch.

Lubricants: the die cavities and the lubricants always have friction especially when the die cavity is eroded by dying. Lubricants are therefore used to reduce that friction that exists during that time. A case like fragmentation, scratching of the tablets back as well as capping can be problems that may be associated with the lack of tablet lubricants. Hence to avoid these problems, lubricants ought to be used.

Pharmaceuticals development have brought a revolution in human health, they can serve their intent if they are free from contaminant/impurities. To allow the pharmaceutical drugs/tablets to do it duty correctly various instrumental and chemical methods have been developed at various stages such as development, transportation and storage to minimise the contamination. (Siddiqui, AlOthman and Rahman, 2017)

Different techniques of characterization, as well as their analytical methods in regard to the analysis of the pharmaceutical tablet, are as discussed below;

3.1 Raman Spectroscopy for Pharmaceutical Drugs

Raman Spectroscopy is becoming one of the most popular analytical measurement tools for pharmaceutical applications ranging from verification of raw materials to process monitoring of drug/tablets production to quality control of products. Similar to an infrared spectrum, a Raman spectrum consists of a wavelength distribution of peaks corresponding to molecular vibrations specific tothe sample being analysed. Chemicals,, such as drugs in the Pharmaceutical tablets, can be identified by the frequency and quantified by the intensity of the peaks. In practice, a laser is focused into the sample, the inelastic scattered radiation (Raman) is optically collected and directed into a spectrometer, which provides wavelength separation, and a detector converts photon energy to electrical signal intensity. An attractive advantage to this technique is that samples do not have to be extracted or prepared, and the laser can simply be aimed at a sample to perform chemical measurements, which can often be accomplished in a minute or less (Stuart Farquharson, 2017).

Raman Spectroscopy

The inelastic light scattering phenomenon is known as Raman radiation. Raman spectroscopy provides information about molecular vibration this is used to identify unknown samples. Raman Spectroscopy involves concentrating a laser (monochromatic light) onto a solid sample and detecting inelastic scattered light, the majority of the scattered light comprises radiation of the incident frequency this process is known as Rayleigh scattering or elastic scattering. (Vankeirsbilck et al., 2002)

A very small quantity of scattered light roughly 0.0001% with shifted frequency is observed, this is due to the interaction of incident radiation waves and molecules vibrational energy in the sample. Photons scattered with less energy before interaction is called Stokes scattering and photons with greater energy is called anti-Stokes. This is described in the figure below. Raman spectrum of the sample is the plotting of frequency vs shifted light and this can be interpreted in the same way as infrared absorption spectrum is interpreted. (Vankeirsbilck et al., 2002)

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Figure 16: Energy transition in Raman spectroscopy

There are two major Raman spectroscopy technologies which are used to collect the Raman spectra this include: Fourier transform Raman (FT-Raman) and dispersive Raman described in the table below. Both of these technologies are important in the pharmaceutical area. (Vankeirsbilck et al., 2002)

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Table 1: Comparison between two Raman technologies.

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Figure 17: Raman Spectroscopy schematics of the equipment.

Advantages and Disadvantages of Raman Spectroscopy

Advantages

Commonly used for quality control of the active ingredient normally require very little and no sample preparation. The technique also provides significant cost savings. The spectra can be achieved non-invasively (bulk and the final product can be tested directly in their packing) and it is a non-destructive method. Raman spectroscopy can be used to study small particle within the tablets or the percentage of active ingredient. Easily identify the chemical structure and applicable for various materials. The sample could be aqueous or solid The process is quick and very quick feedback from the quality team. Disadvantages - there are few limitations which are summarised below.

- The main obstacle for Raman spectroscopy is the cost of required equipment.
- High levels of fluorescence especially when the incident light goes to blue.
- The sample can thermally decompose when the excitation intensities are too high.
- Low-excitation probability: 1 per 10[7]

Pharmaceutical tablet Quality by Raman Spectroscopy

The quality of the manufactured drugs/tablets starts with the verification of the purity of raw materials and finished with the product quality. It is very important for the pharmaceutical tablet to have the right amount of active ingredients, additives and excipient. To maintain the correct product quality Raman spectroscopy is used by the industries to inspect individual products before shipments. (Stuart Farquharson, 2017)

Excedrin is a Pharmaceutical tablet and it is composed of three Active Pharmaceutical Ingredient: Acetaminophen 44%, aspirin 44% and caffeine 12%. The composition of sample tablet can be measured by fitting a Raman spectrum with the spectra of pure Excedrin tablet. This is shown in the figure below. (Stuart Farquharson, 2017)

Excedrin Sample 3 Excedrin Predicted

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Raman Shift 1 l/cm>

Figure 18: A shows the Raman spectra of all the components in Excedrin and B - Raman spectrum for a spot on an Excedrin compared with the Predicted Excedrin. (Stuart Farquharson, 2017)

Most pharmaceutical tablets are non-uniform and a single measurement can lead to inaccurate results. In the case of Excedrin tablet, measurement at 200-micron diameter indicated the different composition of APIs. This is normally overcome by spinning the tablet or using a spot size or transmission Raman. Figure 19, shows the composition of APIs after 20 measurements which tend to match with the predicted Excedrin composition.

Figure 19: shows the composition of APIs after 20 measurements

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The result illustrates that Raman spectroscopy is an excellent technique for verifying the purity of the raw material and the finished product. It is good for calculating the composition of active ingredient in the tablet as It is very important for the pharmaceutical tablet to have the right amount of active ingredients, additives and excipient in order for the tablet to do it duty properly.

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