The development of oral liquid (beverage) mainly focuses on the coordination of taste and efficacy components, in order to find a good taste and bright color and high efficacy components of the optimal ratio, and at the same time, to solve the oral liquid appeared to produce precipitation, turbidity, dark color, gas production and other issues. The main work is formula screening, pilot test, content determination, stability test, costing, product description, etc., to formula screening, sugar selection, precipitation problems are summarized in detail.

Formulation screening

Formulation screening is the most critical step in the oral liquid product development report, which is based on combing the relevant oral liquid products proposed for the population, indications, to clarify the efficacy of the oral liquid products, the efficacy of the product screening in the former State Food and Drug Administration website, collect the relevant formulations after the synthesis of all the information for the generalization and analysis, with the guidance of the theory of traditional Chinese medicine, to exclude the eighteen anti-nineteen fear, and at the same time refer to the modern knowledge of Chinese medicine chemistry, comprehensive formulation of With the guidance of Chinese medicine theory, excluding eighteen anti, nineteen fear, while referring to the modern knowledge of Chinese medicine chemistry, synthesize and formulate the formula. For example, Salvia miltiorrhiza and Lycium barbarum are paired together to prove that there is no problem with the traditional Chinese medicine theory, but with the modern knowledge of traditional Chinese medicine chemistry, we can know that the three paired together will produce precipitation problems.

On the one hand, the active ingredient of Salvia miltiorrhiza is phenolic acid compounds, with o-diphenol hydroxyl structure, in aqueous solution, the charge density of o-diphenol hydroxyl increases, it is easy to dissociate the formation of oxygen-negative ions, and auto-oxidation occurs to generate colored quinones, so that the clarity of the oral solution of traditional Chinese medicine is reduced.

On the other hand, phenolic acid compounds containing phenolic hydroxyl group is easy to form hydrogen bonds with protein molecules, alkaloids and polysaccharides in the solution, generating insoluble precipitates, making the medicine turbid and affecting the clarity of oral solution.

Formulation screening should synthesize the traditional Chinese medicine theory of contraindications (eighteen anti, nineteen fear), modern knowledge of the chemistry of Chinese medicine (structure and reaction of the active ingredient), the former State Food and Drug Administration published information (health care formulas and efficacy of the ingredients) in order to achieve the desired results.

Sugar selection

In the oral liquid product pilot test can be based on different tastes and the needs of specific groups of people to choose different sugars, sweeteners to choose to refer to the previous summary of the ” Comparative Analysis of Various Sugars and Sweeteners: Containing Sweetness, Stability, Sweetness and Other Indicators, there is no more complete than this!

Precipitation problem

Oral liquid has the advantages of fast absorption, rapid effect, can be produced in large quantities, eliminating the trouble of decoction, convenient application, can be added to the flavoring agent, good taste, easy to accept by the patient, etc., is a class of dosage forms widely used in clinical practice. In recent years, due to the increasing number of reports on the clarity of oral liquids, the whole society has begun to explore the problem of the clarity of oral liquids of traditional Chinese medicine, but it is generally limited to the problem of clarity during the production process, without analyzing the problem of clarity that is likely to occur during the storage period.

Improving Clarity

Oral liquid in the early stage of the inevitable turbidity, precipitation and other problems, oral liquid refining in addition to impurity is to ensure that the oral liquid liquid clarity of the key steps. The following methods are summarized below:

I. Alcohol precipitation method
Alcohol precipitation is a commonly used refining method. It can remove some macromolecular impurities and retain the water-soluble and alcohol-soluble active ingredients are better. However, it will cause the loss of proteins, polysaccharides, trace elements, some small water-soluble active ingredients, as well as the residue of ethanol, which directly affect the efficacy. In addition, alcohol precipitation process consumes a large amount of alcohol, high requirements for equipment, the product viscosity is large, easy to absorb moisture, sticky wall, emulsion and other phenomena.

Second, high-speed centrifugation
High-speed centrifugation is a physical separation method, often used to replace the alcohol precipitation method to remove impurities. Centrifugal speed is an important factor affecting the clarity of oral liquid. Centrifugal speed will affect the content of some active ingredients, that the preparation of oral preparations to 4000-6000 r/min speed is appropriate.

Clarifier adsorption method
Flocculants (clarifiers) can remove the suspended particles in the liquid, and the use of natural colloids to keep the preparation clear.

(A) chitosan
Chitosan can effectively retain the active ingredients in the solution, resulting in good clarity and stable quality of the finished product. Chitosan has strong adsorption effect on protein, sugar, tannin, pigment and bacteria. Chitosan has strong adsorption effect on proteins, sugars, tannins, pigments and bacteria. It has trapping effect on heavy metals in traditional Chinese medicine compound, and has no effect on trace elements such as calcium, manganese and zinc, etc., and it can maintain good taste, which is an effective method to improve the quality of medicine. It is an effective way to improve the quality of drugs. The clarity of the liquid is related to the proportion of chitosan added, temperature, stirring and standing time, pH value and the content of raw drugs in the liquid.

(ii) Juice clarifiers
101 fruit juice clarifier is mainly composed of modified starch, water-soluble gelatinous substances. 101 fruit juice clarifier refined Chinese medicine water extract, and alcohol precipitation process for comparison, dry extract yield, the content of the main ingredients and the appearance of the preparation are better than alcohol precipitation. The general use of concentration of 5%, the use of 8% -10% is more appropriate, the amount of medicine containing raw medicine 1:1.5-2.0 is appropriate. Add 0.5% talc in 101 clarifier, can accelerate precipitation filtration, improve the clarity of the solution.

(iii) ZTC1+1 natural clarifier
ZTC1 +1 natural clarifying agent is a new type of food additives, colloidal unstable components of the one-step removal rate of about 70%, two-step removal rate of more than 90%, without affecting the flavonoids, alkaloids, glycosides, terpenes, polysaccharides, vitamins, minerals and other active ingredients, widely used in the preparation of oral liquid.

ZTC1+1 clarifier removes protein and other impurities while effectively retaining the polysaccharide, can be applied to the separation of polysaccharides. Traditionally, polysaccharides are precipitated with 3-5 times the amount of ethanol, and monosaccharides are not precipitated, but proteins are also precipitated. If ZTC1+1 clarifier is used to remove the protein before ethanol precipitation, it is an ideal method to purify polysaccharides. However, in the treatment of starch-containing liquid, ZTC1+1 clarifier and chitosan need to be used in conjunction with other refining methods in order to achieve better clarification.

(D) gelatin – tannic acid method
Extracts often contain a large amount of tannins, tannins are soluble in water and alcohol, it is easy to be oxidized to produce precipitation, change the clarification of the liquid. Gelatin in acidic conditions can be removed from the precipitation of tannin, but also with the concentrate in the gum, pectin, cellulose and other negatively charged impurities produce precipitation.

Fourth, large pore adsorption resin method
Macroporous adsorption resin method is through physical adsorption from aqueous solution selectively adsorbed organic substances to achieve the purpose of separation. Commonly used in saponin, flavonoids, insecure quinone, alkaloids, water-soluble phenolic components of the extraction and purification.

V. Adjustment of pH value
pH value is related to the stability of liquid preparations and preservatives preservative effect. When the solution is more alkaline, alkaloids are easy to be precipitated, and when it is more acidic, some saponins are easy to be precipitated. The clarity of oral liquids is significantly affected by pH value. The pH value of the solution should be adjusted to 4-5 for alkaline active ingredients (e.g. alkaloids) and to pH 7-8 for acidic ones.