Method for Checking the Water Content in the Development of Solid Dosage Forms

Medicines are the foundation for human survival and social development, and are related to people’s lives, health and safety. In the research and development of solid dosage forms, some drugs need to be treated with water, and some need to be added with a certain amount of liquid excipients. Improper operation will affect the quality and hardness of the preparations. At the same time, there are certain safety hazards. Therefore, check the contents of the pharmaceutical preparations. The moisture content is critical. In order to remove the water in the preparation, some companies have spent a lot of thought and price, but in exchange it is the result of the product’s quality guarantee for at most several months.

Since the water content of the drug may affect the stability, physical and chemical properties, and physiological effects of the drug preparation, the quality standards in the development of most APIs and solid preparations require a water check item. Medicilon provides new drug research and development outsourcing services. It has the preparation process and quality research of tablets, injections, capsules, granules, ointments, creams, sprays, gels, syrups, tinctures, oral liquid preparations, etc. Commonly used equipment and instruments, as well as the GMP pilot plant for oral solid dosage, it also has the ability to develop new technologies such as sustained and controlled release preparations, nano preparations, and fat emulsions.

Medicilon provides R&D and production services for pharmaceutical preparations. According to the characteristics of the dosage form, combined with the physical and chemical properties and stability of the drug, the production conditions and equipment are considered, process research is carried out, the preparation process of laboratory samples is initially determined, and the corresponding Process control indicators.

The commonly used methods for determining the moisture content of drugs are mainly as follows.

Karl Fischer titration

The water content is determined based on the principle that iodine and sulfur dioxide react quantitatively with water in pyridine and methanol solutions. This method can be applied to any drug that can be dissolved in the Fischer test solution but does not react chemically with the Fischer test solution. Therefore, this method can still be used for the determination of samples that are easily damaged by heat. When measuring, first dissolve the sample in the prescribed solvent and then titrate. Normally, all the water in the sample is released into the solvent, so the measurement result includes two parts: adsorbed water and bound water.

However, it should be noted that some oxidants such as chromate, reducing agents such as thiosulfate and other compounds that can form water with the test solution will interfere with the determination; some carbonyl compounds also interfere with this method: active aldehydes and ketones and reagents Methanol reacts to form acetal and water, causing the test result to be high.　

Determination of loss on drying

The loss on drying of a drug refers to the percentage of weight loss of the drug after drying under specified conditions. It mainly refers to moisture, crystal water and other volatile substances. The loss on drying of the test product is calculated from the weight loss and the sample amount. The loss-on-drying method measures the weight loss of a sample after drying under normal pressure or reduced pressure. The loss is mainly moisture except for a very small amount of organic solvent.

This method can accurately determine the moisture content of most drugs, but when the sample contains crystal water, especially when the crystal water is closely bound to the drug molecules, the result of the determination is often not the total amount of water in the sample, but only adsorbed water.

Thermogravimetric analysis method（TGA）

Thermogravimetry, also known as thermogravimetry, is a technique for measuring the relationship between the weight of a substance and the temperature under program-controlled temperature. Under normal circumstances, this method is suitable for the determination of drug crystal water and the analysis of weight loss on drying of precious drugs (with a small sample amount) or drugs that are easily oxidized in the air. Like the loss-on-drying method, this method also uses heating to make the sample weightless, but uses a program to control the temperature. The advantage is that the amount of sample required for the measurement is smaller, the analysis time is shorter, the data processing is more convenient, and the amount of information obtained is large. . However, when the crystal water and the drug molecule are very tightly bound, the crystal water is released when the drug melts and decomposes. The measurement result at this time is likely to cause the illusion that there is no crystal water in the sample.

Differential scanning calorimetry

This method is a technique to measure the relationship between the energy difference and temperature (or time) between the substance to be measured and the reference substance under the program control temperature. When the sample contains crystal water, there will usually be obvious absorption in the spectrum. Hot peak. However, when the crystal water is tightly bound to the sample molecules, the endothermic peak of the crystal water may overlap with the melting endothermic peak of the sample.

Single crystal X-ray diffraction method

It is possible to accurately determine whether crystal water is bound in the sample under this crystal form and the way of binding, but the disadvantage is that the preparation of single crystals is difficult, time-consuming, and sometimes even unable to obtain single crystals, so this method has certain limitations.

In summary, it is recommended that the following principles should be followed when choosing a conventional moisture determination method:

(1) When the sample is easily soluble in methanol or pyridine and does not interfere with the titration, the Fischer method is preferred;

(2) If the Fisher method is not suitable for measuring the moisture of the species under the conventional test conditions, the loss on drying method can be considered, but in the methodological research, it is recommended to use the Fisher method, thermogravimetric analysis method, and differential scanning volume. Thermal method, combined with literature reports for comprehensive analysis and verification;

(3) For drugs with new structures, single crystal X-ray analysis is recommended to confirm the binding mode of water in the sample, so as to provide an accurate chemical structure basis for later quality research, stability research and physiological activity research.

Related Articles:

Analysis on the Composition and Preparation Process of Oral Solid Dosage Forms

Dosage Research and Common Dosage Forms

The Spray Drying Method of Solid Dispersant Preparation Technology