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Pharmacology: a brief history
Our search for medicines is nearly as old as humanity itself. Medicinal ingredients from plant, mineral, and animal sources were used for healing purposes since the earliest of advanced civilizations. Herbal remedies from China date back to a couple of thousand years ago, while indigenous populations have been relying on environmental sources for healing for several millennia. Systematic descriptions of medicines have been handed down to us from the ancient Greeks and the Roman Empire, laying a foundation for contemporary pharmacology. It was not until the 16th century that the science began its departure from the models passed down from antiquity.
The path to developing synthetic drugs began with the emergence of organic chemistry at the beginning of the 19th century. Although drug therapies had been limited to naturally occurring substances and inorganic compounds up to that point, this changed with the targeted production of organic synthetic drugs based on substances isolated from medicinal plants. Within a very short period, this led to a vast number of synthesized active pharmaceutical ingredients (APIs). Researchers had finally come to understand the relationship linking the action of these substances to their chemical structures.
Pharmaceutical analysis provides information about the identity, purity, content, and stability of starting materials, excipients, and APIs. Medicinal products come in various forms (e.g., ointments, tinctures, pills, lotions, suppositories, infusions, sprays, etc.) and consist of the active substance and at least one pharmaceutical excipient. Impurities are mainly introduced during the synthesis of the active ingredients.
According to the World Health Organization (WHO), specifications and test methods for commonly used active ingredients and excipients are outlined in detail in monographs contained in the national pharmacopoeias of more than 38 countries. The pharmacopoeias are official compendia containing statutory requirements pertaining to identity, content, quality, purity, packaging, storage, and labeling of active pharmaceutical ingredients and other products used for therapeutic purposes. They are essential for anyone seeking to produce, test, or market medicinal products.
Near-infrared spectroscopy—a 21 CFR Part 11 compliant tool to assess the quality of pharmaceuticals
Near-infrared spectroscopy (NIRS) has been an established method for fast and reliable quality control within the petrochemical industry for more than 30 years. However, many companies still do not consistently consider the implementation of NIRS in their QA/QC labs. The reasons could be either limited experience regarding application possibilities or a general hesitation about implementing new methods.
However, the advantages of NIRS are numerous, such as the ability to measure multiple parameters in just 30 seconds with no sample preparation! The non-invasive light-matter interaction used by NIRS, influenced by physical as well as chemical sample properties, makes it an excellent method for the determination of both property types.
In the remainder of this post, we will indicate where NIRS technology can be used in the pharmaceutical production process and what parameters can be analyzed. Furthermore, we present proven applications developed according the NIRS implementation guidelines of ASTM E1655 (quantitative method development) and ASTM E1790 (qualitative method development).
For more detailed information about NIRS as a secondary technique and NIRS as a QC tool for pharmaceuticals, please read our previous blog posts.
NIRS compliance with international pharmacopoeias
As a secondary test method, NIRS is recommended in all the key pharmacopoeias – European (Ph. Eur. 2.2.40) as well as American (USP<856/1856>) and Japanese pharmacopoeias (Chapter 6, since 2007).
All Metrohm NIRS instruments are fully compliant with USP <856/1856> and all the other key pharmacopoeias. Furthermore, all Metrohm NIRS instruments meet the standards for wavelength precision, reproducibility, and photometric noise. Numerous reference standards and user-friendly software make it easy to check the instrument requirements specified in the pharmacopoeias. The pharmaceutical version of the Vision Air software is fully validated and compliant with 21 CFR Part 11.
Find out more about Metrohm NIRS instruments for laboratory and process analysis below.
Where can NIRS be used in pharmaceutical manufacturing processes and what parameters can be analyzed?
NIRS is an indispensable analysis technique that can be used along the entire production chain: from checking the incoming materials to the production line, even to the quality control of finished products. A typical pharmaceutical tablet production process is shown in Figure 1 with markers noting where NIRS can be implemented.
Typical NIRS applications at the different stages of the pharmaceutical production process are outlined in Figure 2.
Relevant Metrohm Application Notes for the pharmaceutical inudtry can be found in the link below.
Applications and parameters for NIRS in pharmaceutical production
NIR spectroscopy is the fast solution for determining myriad parameters simultaneously in almost any sample matrix. In addition, this technique requires no sample preparation, and it is non-destructive. Table 1 contains a list of different administered forms of medications given with commonly measured parameters and related materials to download for more information.
Table 1. NIRS can be used to determine several parameters in many kinds of administered forms of pharmaceuticals.
| Substance form | Parameter | Conventional method | Related NIRS Application Notes |
|---|---|---|---|
| Powders or granulates |
API, Moisture |
HPLC / GC / KF titration |
|
| Tablets and capsules |
API, Content uniformity, Moisture content, Dissolution profile |
HPLC / GC / KF titration |
|
| Creams or gels | API, Moisture content | HPLC / GC / KF titration | AN-NIR-020 |
Solutions or suspensions |
API |
HPLC / GC |
|
| Injectables | API | HPLC / GC | AN-NIR-042 |
| Lyophilized products | Moisture content | KF titration | AN-NIR-078 |
Following are a few examples of successfully implemented NIRS applications at numerous pharmaceutical companies worldwide.
Incoming (raw) material inspection
Raw material identification and qualification, shown in Figure 3, is one of the most mature applications in the pharmaceutical industry. Good manufacturing practice requirements demand that every single package unit that arrives in the warehouse needs to be checked. Therefore, a rapid analytical technology as NIR spectroscopy is needed to measure many samples in a short period of time. NIRS is a general accepted alternative method by the USP.
NIRS is an ideal analytical method for raw material inspection:
- identify tests of APIs, excipients, packaging
- quantitative control of materials (e.g., moisture)
- GMP Requirement to test 100% of raw materials
- quality control of materials (e.g., supplier, particle size, dyes)
Blending
Blending of APIs and excipients can be easily monitored without sample destruction by NIRS (Figure 4). This application focuses on the standard deviation between consecutive spectra. As the blending proceeds, the differences between consecutive spectra will become smaller and smaller, approaching unity. This parameter indicates when the blend is homogeneous. This information is important for operators to optimize the blending time and consequently increase the blending capacity of a facility.
NIRS is an ideal analytical method for blending processes:
- determination of blend homogeneity
- sample spectra statistically compared to library of well blended material
- optimized blending for improved operation of next production steps
Learn more about the Metrohm NIRS DS2500 Analyzer here.
Lyophilized products
Moisture determination in lyophilized products is an ideal application for NIRS (Figure 5). Typical water content of lyophilizates is somewhere between 0.5% and 3.0%. For many pharmaceutical lyophilized products, this value must be lower than 2.0%. Water is a strong NIR absorber, so detection limits are low and the demands of the pharmaceutical industry can be easily met.
Primary methods like loss on drying (LOD) or Karl Fischer titration are typically time-consuming, especially compared to NIRS (data in seconds). These samples have a relatively high value combined with a low moisture content. NIRS analysis only illuminates the sample so the same sample can be used for compendial analysis without any damage. This application has a quick return on investment (ROI) due to the high sample frequency.
NIRS is an ideal analytical method for measuring moisture in lyophilized products:
- samples can be easily altered to provide calibration sets with varying amounts of moisture
- complete analysis takes less than one minute and is non-destructive
Tablet analysis
When analyzing intact tablets with a NIR spectrometer, it is important to measure them in diffuse transmission mode. This illuminates a larger sample big portion and investigates the inner composition of the tablet (Figure 6). Measuring the same tablet in reflectance mode will gather the information from the outside coating of the tablet due to the low penetration depth. Content uniformity parameters are measured within a minute, and the tablet trays allow unattended measurement of up to 30 tablets.
Learn more about the differences in NIRS measurement modes in our previous blog post.
Summary
Near-infrared spectroscopy has long been one of the most important and versatile analytical techniques in the pharmaceutical industry. The biggest benefit of using NIRS is the possibility of obtaining reliable analysis results in just seconds without any sample preparation or reagents required.
The pharmaceutical version of Vision Air software from Metrohm is 21 CFR Part 11 compliant and compatible with third party method development software like Unscrambler.
