Overview of Testing in the Pharmaceutical Industry

1. The Importance of Pharmaceutical Quality Control

The pharmaceutical industry is an important part of China's national economy — an industry combining traditional and modern industries and integrating the primary, secondary and tertiary sectors. Its main categories include: chemical raw materials and preparations, Chinese medicinal materials, prepared Chinese herbal pieces, Chinese patent medicines, antibiotics, biological products, biochemical drugs, radiopharmaceuticals, medical devices, sanitary materials, pharmaceutical machinery, pharmaceutical packaging materials and pharmaceutical commerce. The pharmaceutical industry plays a very important role in protecting and improving people's health, enhancing quality of life, supporting family planning, disaster relief and epidemic prevention, military supplies and preparedness, and promoting economic development and social progress.

Pharmaceuticals are a special kind of commodity whose quality is directly related to human life and health. From the transportation, warehousing and transfer of pharmaceutical raw materials, to every step of the production process, to the quality and packaging of finished drugs, strict control must be exercised — a reliable and effective measure to ensure drug quality and medication safety. With socio-economic development and the continuous improvement of people's material and cultural living standards, people have increasingly higher requirements for medical quality, and pharmaceutical companies are increasingly aware of quality control in every step of drug production. The 2017 new edition of the Pharmacopoeia and strict FDA and GMP certification requirements also impose higher demands on drug quality testing.

2. The Significance of Moisture Content Control in Pharmaceuticals and Solutions

Water is the medium of chemical reactions, and many reactions do not proceed without it. For solid preparations with poor chemical stability, a liquid film is adsorbed on the solid surface due to humidity and moisture, and the drug degrades in the liquid film — examples include vitamin C tablets, acetylsalicylic acid tablets, vitamin B12, penicillin salt powder injections and ferrous sulfate. In general, the degradation rate of solid drugs affected by moisture is proportional to relative humidity: the higher the relative humidity, the faster the reaction. Besides causing chemical reactions in drugs and raw materials, excessive moisture also makes raw materials and drugs prone to mildew and deterioration, seriously affecting drug quality and shelf life. Therefore, moisture should be strictly controlled during the transportation and warehousing of pharmaceutical raw materials, as well as during production and storage.

2.1 Moisture Content Determination Methods in the Pharmaceutical Industry

There are many methods for determining moisture content. Moisture analyzers commonly used in the pharmaceutical industry include loss-on-drying (loss-on-heating) moisture analyzers — mainly halogen moisture analyzers and far-infrared moisture analyzers — and Karl Fischer moisture analyzers: volumetric Karl Fischer moisture analyzers and coulometric Karl Fischer moisture analyzers.

2.1.1 Introduction to the Loss-on-Drying Method

The loss-on-drying method uses physical analysis to determine moisture content by exploiting the effect of temperature on moisture volatilization to dry out the moisture in the material. The internationally common determination method is the oven method: the material sample is placed in an oven for drying, weighed on an electronic balance, and the moisture value is calculated manually. This method takes 2-4 hours per sample. For companies with high-paced production, the oven method seriously affects production efficiency and can no longer meet their needs.

Against this background, VicoMeter moisture analyzers use high-efficiency drying heaters — high-quality ring halogen lamps or far-infrared dark-field ring heaters — to heat samples instead of traditional oven heating, increasing heating speed several times over. This method features fast heating, uniform heating and long service life. VicoMeter has integrally upgraded the oven drying method, perfectly combining the heating module, weighing module, operation module and human-machine intelligent module. The system can intelligently stop based on the measurement trend and analyze the sample moisture value, displaying the result directly on the screen, truly achieving one-button testing. The results show good consistency with the oven method, and most samples can be measured in just a few minutes, with work efficiency far higher than the oven method — widely favored and praised by enterprise users.

2.1.2 Introduction to the Karl Fischer Method

The Karl Fischer method has two variants: titration (volumetric) and coulometric, and is an analytical method for moisture determination proposed by Karl  Fischer. Among the various chemical methods for determining moisture in substances, the Karl Fischer method is the most specific and accurate for water. Improved in the market in recent years with higher accuracy and an expanded measurement range, the Karl Fischer method has been listed as a standard method for moisture determination in many substances.(Go to "The Karl Fischer Method" for details)

Chemical Reaction Principle of the Karl Fischer Method

When iodine oxidizes sulfur dioxide, a certain amount of water is required for the reaction: I2+SO2+2H2O=2HI+H2SO4  , and this reaction is reversible. To drive the reaction forward quantitatively, an alkaline substance must be added. Therefore, methanol or another solvent with an active OH group must be added to the reagent to convert pyridine sulfur trioxide into stable pyridinium methyl hydrogen sulfate.

In KF coulometric titration, the required iodine is generated directly by electrolysis; water content is calculated from the charge-iodine relationship. When free iodine appears, the voltage across the Pt indicator electrodes drops sharply—marking the endpoint.

Electrolysis Reaction of the Karl Fischer Method (Faraday's Law of Electrolysis)

During electrolysis, the electrode reactions are:

Anode: 2I--2e→I2          Cathode: I2+2e→2I-, 2H++2e→H2↑

From the above reactions, it can be seen that 1 mol of iodine oxidizing 1 mol of sulfur dioxide requires 1 mol of water — equivalent to an equivalent reaction of 1 mol iodine with 1 mol water. Electrolyzing 1 mol of iodine requires 2×96493C of electricity (Faraday constant 9.6493×10000C/mol), and 1 mol of iodine can consume 18g of water.

From Faraday's law of electrolysis, M×10-6/18=Q×10-3/2*9.6493, so M=Q/10.722

Where: W--moisture content (μg); Q--electrolysis charge (mC); 18--molecular weight of water.

2.1.3 Introduction to Portable Moisture Analyzers

A portable moisture analyzer is essentially an instrument for the rapid testing of material moisture. Its overall accuracy is inferior to that of laboratory moisture analyzers, but it is more reliable and accurate than the touch and experience of a “veteran”. A calibrated portable moisture analyzer can quickly determine the moisture content of a sample on the job site; if a material's moisture content is found to exceed the warning level, it is sent to a professional laboratory for analysis and confirmation with a laboratory moisture analyzer. Thanks to their portability and fast testing, portable moisture analyzers are widely used in incoming material inspection, production sites and spot checks in the pharmaceutical industry.

2.1.4 Online Moisture Analyzers

In the pharmaceutical industry, online moisture analyzers are mainly based on two solutions: microwave and infrared. An online moisture analyzer is also a rapid moisture testing solution; unlike a portable moisture analyzer, it can be installed directly at the job site to monitor material moisture in real time. Enterprises can analyze historical data to improve production processes, or use the moisture warning function to quickly handle on-site moisture overruns.

2.2 Applicable Scenarios and Selection of Moisture Analyzers

In the pharmaceutical industry, the moisture content of various raw materials, intermediates and finished products must be determined. Since the samples to be tested come in various forms — solid, liquid and gas — finished drugs, for example, include tablets, suppositories, freeze-dried products and certain active substances, and moisture exists in different forms in the samples, such as free water and crystal water, while the drug ingredients contained in the samples can also affect measurement. Therefore, when determining the moisture content of drugs, different determination methods should be selected according to the physical and chemical properties of the drugs.

2.2.1 Applicable Scenarios of the Loss-on-Drying Method

The loss-on-drying method is suitable for testing samples that contain no volatile substances other than water and samples that are insoluble or difficult to dissolve in organic solvents, including solids, powders, granules, viscous materials and fluids. In general, a halogen moisture analyzer with higher heating efficiency is preferred, featuring fast heating, uniform heating, high efficiency, energy saving and environmental protection. For temperature- and light-sensitive samples, such as samples with high sugar content, a far-infrared moisture analyzer should be selected, whose heating is relatively gentle and uniform — a traditional heating method.

2.2.2 Applicable Scenarios of the Karl Fischer Method

The Karl Fischer method is suitable for testing samples whose side reactions produce no water and which neither consume nor release iodine themselves. In general, for hydrocarbons, oils, alcohols, halogenated hydrocarbons, phenols, lipids and ethers, a coulometric Karl Fischer moisture analyzer is selected; for organic acids, inorganic acids  , acidic oxides, acid anhydrides, acids, alcohols, esters, stable hydroxyl compounds, acetals, ethers, hydrocarbon anhydrides, acid halides, halides, peroxides, nitrogen compounds and sulfur compounds, a volumetric Karl Fischer moisture analyzer is selected.

Here, VicoMeter summarizes several tips on how to choose between a coulometric and a volumetric Karl Fischer moisture analyzer:

① The volumetric method is suitable for liquid and solid samples; the coulometric method is suitable for liquids and gases.

② When the sample moisture content is below 1000ppm, the coulometric Karl Fischer moisture analyzer is ideal; when the sample moisture content is above 1000ppm, the volumetric Karl Fischer moisture analyzer is ideal.

③ If multiple samples are to be tested and chemical reactions may occur between different samples, the volumetric method is required.

④ Because of complex samples, the pharmaceutical industry generally uses volumetric moisture analyzers.

Since every company's samples are different, we recommend that you do not make a decision hastily. Please contact VicoMeter staff, and we will develop the most suitable testing solution for you based on your actual situation.

3. Application of Weighing in the Pharmaceutical Industry

Weighing (scale) equipment is widely used in the pharmaceutical industry, such as in drug R&D, material inbound and outbound management, raw material production and packaging, drug preparation, inspection, and the production and packaging of preparations. All equipment related to drug production must comply with GMP. Weighing equipment is one of the keys to quality and hygiene safety control in the drug production process, and weighing accuracy throughout the production process is critical, directly affecting the final quality of drugs. If needed, VicoMeter has been deeply engaged in the pharmaceutical industry for many years and can provide users with a full range of weighing solutions.