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Basic Knowledge of Pre-Formulation Research for Injections

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The rational study of the injection pre-formulation should be based on the quality profile of the target product, the physical and chemical properties of the API, and the compatibility of the API and other excipients. The primary packaging system should be determined according to the storage conditions of the product, and the pharmacokinetic characteristics of the API should also be included. .

Pre-formulation research should obtain basic knowledge through preparation research and analytical research together (not just the work of preparation students), and pre-formulation research can also promote and support follow-up prescription research. (For detailed requirements for injections, please refer to “Technical Requirements for the Consistency Evaluation of Listed Chemical Generic Drugs (Injections)”. These technical requirements are not only for generic drugs, but also for new drugs)

In the drug development timetable, pre-formulation research can accumulate data and make data support for subsequent research and development decisions, such as salt form selection, crystal form selection, excipient selection, selection of toxicologically appropriate formulations, and final determination of clinical and The prescription composition of a commercial batch. In addition, full research on the physical and chemical properties of raw materials can often help solve the problems of prescription determination, product stability, and production process parameters. (Injection research also requires sufficient research on the crystal form of the bulk drug)

A full understanding of the physical and chemical properties of APIs is the first step in “Quality comes from design”. Researching APIs at different levels, such as molecules/materials/macro, can help us better understand the properties of Yuan’s APIs. Table 1 shows the hierarchical structure of this physical and chemical property. Usually the target dosage form determines the research focus. For solid dosage forms, it is important to understand the macroscopic properties of the bulk drug, but for injections, it is usually more important to understand the molecular and material properties of the bulk drug.


Note: The molecular properties of chemicals can be predicted by some predictive software at the beginning, such as solubility and pH-solubility curves.

Solubility is not only very important in the development of solid preparations, but also a very critical parameter in the development of injections. However, the solubility of many drugs may be unsatisfactory. The following briefly introduces several methods to improve the solubility of APIs:

Co-solvent system improves solubility

Co-solvent systems such as ethanol, propylene glycol, polyethylene glycol, and glycerin are commonly used to mix with water to prepare a co-solvent system to improve the solubility of the drug substance. The mechanism of co-solvent system to promote dissolution is usually related to “similar dissolution”, that is, polar molecules are easy to dissolve in polar systems, and weakly polar molecules are easy to dissolve in weakly polar systems.

Although co-solvents play a great role in promoting dissolution, it should be noted that some co-solvents are toxic (such as hemolysis) and local irritation. Also note that the co-solvent system may have the possibility of drug substance precipitation once it is diluted. Experiments can be carried out in advance to evaluate the possibility of precipitation in the co-solvent system after dilution.

Surfactant system improves solubility

Surfactants usually refer to amphiphilic molecules (hydrophilic head and lipophilic tail). When the solution reaches a certain concentration, micelles are formed, and lipophilic drugs are encapsulated in the core of the micelles. . The core of the micelle creates a different environment for lipophilic drugs. To some extent, the core of the micelle can act as a stabilizer. AmBisome B (AmBisome) developed by NeXstar Pharmaceuticals in the United States is the world’s first liposome product to be marketed, and Paclitaxel Liposome Injection (Lipusu) is marketed in China.

Complex system improves solubility

A complex is a whole composed of two molecules, such as a drug molecule and a solubilizing ligand through a weak non-covalent bond (dipole-dipole, hydrophobic or hydrogen bond interaction). Cyclodextrin is a classic representative among them, and it has been importantly used in drug research and development. From the perspective of formulation development, cyclodextrin can be combined with poorly water-soluble drugs to increase the solubility of drugs. It is a good way to improve the solubility of drugs. HP-β-CYD has been included in the United States Pharmacopoeia. Excipients for injection.

Stability and drug degradation

In addition to solubility, the stability of the drug substance is also a key determinant in the formulation of injections. Because first, the drug needs to maintain the same dosage as in the instructions during the shelf life, and second, the degradation of the drug may cause changes in appearance (color or precipitation) or bioavailability. Finally, the degradation products of APIs may also be toxic or harmful to the body (refer to ICH Q3B(R2) for details). When product degradation products or impurities are identified as potentially genotoxic, they need to be controlled within a very low limit if they cannot be completely avoided. For details, please refer to the EMEA guidelines. Therefore, it is very necessary to understand the degradability and degradation products of the bulk drug itself, as well as the degradability and degradation products of the bulk drug in the formulation.

Degradation mechanism: There may be many reasons for the degradation of small molecule drugs, but most of the degradation pathways can be classified as hydrolysis (mostly related to the pH of the solution, so it is necessary to study to determine the most stable pH of the solution), oxidation (if there are oxidation problems) , It is necessary to study nitrogen or other inert gases or adding antioxidants) and photodegradation (for drugs that are easily oxidized and deteriorated due to light, during the production and storage process, light exposure should be avoided as much as possible, or directly stored in colored light-shielding containers) . The degradation of APIs may cause many problems, which need to be analyzed in detail based on the specific problems of the API degradation mechanism.

Pre-formulation stability study: usually study the stability of the bulk drug in solid and solution states. For details, please refer to ICH Q1B.

Form screening of APIs

The solid form of the bulk drug has an important influence on the injection process. Regardless of the late discovery or early development stage, the solid form of the API must be clearly studied and determined so that the physicochemical properties of the API used in subsequent formulation research and process development meet the corresponding requirements. The solid form of the drug substance usually refers to the salt base and the crystal form after salt formation.

Base selection: Many drugs are either weak acids or weak bases, so they can form salts with a variety of acids or bases. After salt formation, it can change the physicochemical properties, pharmacokinetics and technological properties of the raw materials without changing the groups that exert their pharmacodynamic effects. In order to form a stable salt, the pKa of the drug before salt formation should be two or more greater than the pKa of the conjugate acid with which it forms the salt. This also helps determine which salt is appropriate.

For injections, salt formation is usually used to increase the solubility of the drug substance. In addition, it is not necessary to prepare the raw material into a salt before the product is produced, and it is also possible to add the corresponding acid or base to the solution to form the corresponding salt during the production of the injection.

Crystal form selection: The research and development of solid preparations generally pay a lot of attention to the crystal form of the bulk drug. This is because the crystal form affects the bioavailability of the solid preparation and the selection of the preparation process. However, the development of injections also needs to pay attention to the crystal form of the API, because different crystal forms of API have different solubility, different dissolution rate, and different hygroscopicity. It should be noted that the most stable crystal form has the lowest solubility. If the raw material of the metastable crystal form is used in the injection or suspension, it is necessary to pay attention to the risk of crystallization during the storage period of the product (by Conversion of metastable crystal form to stable crystal form). Solvent maturation studies and product temperature cycling studies can help identify these problems as early as possible.

When solvent molecules are inserted into the crystal lattice of the drug, solvates are formed, and when the solvent is water, hydrates are formed. Hydrates are generally more stable than anhydrates, but at the same time their solubility will also decrease. Therefore, it is also very important to understand and identify the solvent or hydrate of the drug.

Compatibility of raw materials

Many excipients are used in the design of injection prescriptions. Some excipients are used to increase the solubility of the drug, or to increase the physical or chemical stability of the preparation, or to control other properties of the preparation. The use of new excipients may require additional pharmacological and toxicological evaluations. (For the maximum dosage of excipients for specific routes of administration, you can refer to the FDA’s iig database, but a satisfactory answer is often not obtained)

It is now possible to use DSC or isothermal heat conduction calorimetry to study the compatibility of raw materials and auxiliary materials (to investigate whether the raw materials and auxiliary materials are reacted) to obtain first-hand information, but the information obtained by these methods is sometimes inaccurate. The most commonly used method to study the compatibility of raw materials and excipients is to investigate the stability of products through accelerated conditions.

Compatibility of preparations and packaging materials and production equipment

During the production process, injections need to be in contact with production equipment, such as stainless steel preparation tanks, glass, silicone tubes and filter elements. During storage, the injection should be in close contact with the packaging material. In order to prevent adsorption or incompatibility during production or storage, it is necessary to study the compatibility of the injection with the packaging material and production equipment before prescription. Regarding the selection of packaging materials, you can refer to the “FDA Guidelines for Container Sealing Systems for Packaging of Human Drugs and Biological Products” translated by the Center for Drug Evaluation of the National Medical Products Administration.

The pre-formulation research of the injection is to have as full an understanding of the physical and chemical properties of the raw material as possible, and also to study the compatibility with the excipients and packaging materials, so as to have a general understanding of the subsequent formulation development.


  1. In situ salt screening-a useful technique for discovery support and preformulation studies.

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