​The third series of pharmaceutical excipients-functional indicators of pharmaceutical excipients (FRCs)

In the first article, "For the lips and teeth, things to know about medicinal excipients with more than 100 billion growth space (1)", the editor proposed that some medicinal excipients have certain medicinal effects instead of what people think It is an inert substance and has no pharmacological activity

FRCs have gradually become an important content in the text of pharmaceutical excipient standards

PART 0 1.

Table 1 Common FRCs and FRTs

The functional indicators of the ingredients are often different for different formulations, and the FRCs of the same excipient are often different in different dosage forms and different uses

PART 0 2.

Research techniques for functional indicators of pharmaceutical excipients are generally classified according to the types of excipients

Let's take a brief example to see how the functional research of pharmaceutical excipients is done.

Study on Surfactant Polysorbate 80 FRCs

Polysorbate 80 is widely used in formulations as a solubilizer, wetting agent, emulsifier, and biopharmaceutical freeze-dried protective agent, which is of great significance for the research of its FRCs

Polysorbate 80 is an ester of oleic acid and Span 80 (polyoxyethylene sorbitan), in which the ratio of polyoxyethylene: sorbitol (tan): oleic acid is (20:1:1)

The FRCs of polysorbate 80 are mainly CMC, HBL value, tumble point, fatty acid composition of oleic acid, peroxide value, and sometimes acid value, iodine value, and saponification value are also considered FRCs, but research shows that the first three are particularly critical For high-risk routes of administration, these FRCs are closely related to safety

For the determination methods of fatty acid composition and peroxide value, please refer to the methods included in the Chinese Pharmacopoeia

(1) Critical micelle concentration (CMC)

It is an important indicator for surfactants to perform their functions.

Surface tension method

This is a method with a wide range of applications

Conductivity method (the classic method of measuring CMC)

Only limited to the determination of ionic surfactants

Dye method

The color of some dyes in water and micelles is obviously different
.
The CMC is determined by titration .
First, add a small amount of dye to the surfactant solution of higher concentration (>CMC).
At this time, the dye dissolves in the micelles and presents a certain color
.
Then use the method of titration to dilute the solution with water until the color changes significantly.
At this time, the concentration of the solution is CMC
.

Turbidity Method

Non-polar organics such as hydrocarbons are generally insoluble in dilute surfactant solutions (<CMC), and the system is turbid
.
When the surfactant concentration exceeds CMC, the solubility increases sharply and the system becomes clear
.
This is the result of the solubilization of hydrocarbons after the formation of micelles
.
Observe how the turbidity of the surfactant solution with proper amount of hydrocarbon changes with the concentration of the surfactant, and the concentration of the turbidity mutation point is the CMC of the surfactant
.

Light scattering method

Micelle is an association of dozens or more surfactant molecules or ions, and its size enters the wavelength range of light waves, and has strong light scattering
.
The CMC can be determined by using the mutation point in the scattered light intensity-solution concentration curve
.
In addition to measuring CMC, this method can also measure the aggregation of micelles, the shape and size of micelles
.

(2) The last point

Also known as the cloud point, it is the temperature at which the uniform micellar solution of nonionic surfactants undergo phase separation, which is a very important physical parameter
.
The solubility of non-ionic surfactants such as polysorbates begins to increase with the increase in temperature.
After a certain temperature, the solubility drops sharply, making the solution turbid and even stratifying, but it can return to clarity after cold.
The phenomenon of changing from clarity to turbidity is called the initiation, and this transition temperature is called the initiation point
.

(3) HLB value

The hydrophilic-lipophilic balance value is a relative value.
It is specified that the HLB value of the lipophilic paraffin wax (completely non-hydrophilic) is 0, and the HLB value of the hydrophilic polyethylene glycol (completely hydrophilic) is specified.
20.
Based on this standard, the HLB value of other surfactants is established
.
The smaller the HLB value, the stronger the lipophilicity; on the contrary, the stronger the hydrophilicity
.

PART 0 3.
Summary

The significance of establishing the functional evaluation of pharmaceutical excipients lies in the comprehensive understanding of preparations, excipients, and API
.
The functional study of pharmaceutical excipients is a characteristic study of pharmaceutical excipients.
Just like drugs require safety and effectiveness, excipients should not only be safe, but also ensure their functionality
.