The purpose of preformulation research is to provide a basis for preformulation process design, and to provide clear mechanism and targeted solutions to problems arising in the research of preformulation process. The quality characteristics of the final product are largely determined by the properties of the drug substance. Although there are many ways to optimize the preparation, it is often not as effective as controlling the characteristics of the drug substance. The quality by design (QbD) R&D concept mentions that another important purpose of preformulation research is to provide a basis for preliminary risk assessment for formulation research and to determine the direction and scope of formulation research. This coincides with the trend of moving the control point forward in modern product development.
Therefore, preformulation research is really a “knowing the enemy” research process.
Main content of preformulation research
The main content of preformulation research is to figure out the physical, chemical, biological and mechanical properties of APIs and excipients. Among them, the physical properties of APIs often include: solubility, crystal form, particle size, crystal habit, etc.; the chemical properties of APIs often include: stability, compatibility with excipients, etc.; the biological properties of APIs mainly include: permeability , BCS classification, enzyme metabolism stability, etc.; the mechanical properties of APIs often include: fluidity, compressibility (plasticity and elasticity), density, etc.
Preformulation research also needs to be combined with formulation research to determine the key attribute CQA of the bulk drug. Special attention should be paid to: the influence of the nature of the raw material drug on the preformulation is not only the work of preformulation research, but also the work of preformulation research.
Several elements of preformulation research must be paid attention to:
1 Oil-water partition coefficient
The oil-water partition coefficient (logP) value refers to the logarithmic value of the partition coefficient of a substance in n-octane (oil) and water. It reflects the distribution of substances in the oil and water phases. The larger the logP value, the more lipophilic the substance is. On the contrary, the smaller the value, the more hydrophilic, that is, the better the water solubility. The determination of the oil-water partition coefficient of the drug helps to estimate the in vivo absorption of the drug (biofilm permeability). In order to design a suitable dosage form and route of administration according to its characteristics.
2 Research on dissolution properties
For oral solid dosage forms, most drugs can only pass through the gastrointestinal mucosal wall and be absorbed into the blood circulation when they form a molecular state in the gastric juice or intestinal juice to have a therapeutic effect. Therefore, if the dissolution rate of the drug into the gastric juice or intestinal juice is less than the rate of gastrointestinal absorption, the dissolution process of the drug becomes the absorption limiting step. Therefore, it is necessary to study the solubility properties of the drug. The study of dissolution properties includes the apparent solubility of the drug, the characteristic solubility, the solubility and the dissolution rate in various organic solvents, aqueous solvents, solutions of different pH and different buffer salts, various oils, surfactants, and co-surfactants.
3 Screening and optimization of crystal and salt forms of 3API
The crystalline and salt forms of certain APIs will have a significant impact on the physical and chemical properties of the formulation. The purpose of salt screening is to improve the properties of the prototype (especially solubility); the purpose of crystalline form screening is to select a low-energy thermodynamically stable state to Reduce the risk of physical state changes during production and storage. Balance and trade-offs are unavoidable; sometimes one has to choose a physical state that is not commonly used or is not stable enough. Therefore, the crystal and salt forms of API must be screened and optimized to meet the requirements of preparations and clinical medications.
4 Dissociation constant (pKa) of weak electrolyte drugs
Weakly acidic and weakly basic drugs account for more than 95% of all drugs. Therefore, it is important to understand the dissociation constant of the drug before formula development. Determining the dissociation constant of the drug can infer the solubility and dissolution of the drug in different pH environments, and even the absorption in the body.
5API’s hygroscopicity and influencing factors
Investigate the stability of API to temperature and humidity. For drugs that are sensitive to temperature and humidity, necessary measures need to be taken in formulation development and process development to avoid exposure of the drug to high-temperature and high-humidity environments, and the environmental humidity of the production workshop needs to be controlled during the scale-up process research.
6 Research on powder properties
The study of powder properties has important guiding significance for formulation development, process optimization, quality control, packaging and so on. In the process of powder science research on solid powders, the focus is on the compressibility of the powder, the API crystal transformation that may be triggered by the process, the effect of particle size on the preparation process, the flowability of the powder, and the selection of technical parameters for the preparation process.
7 Compatibility of pharmaceutical excipients
Influencing factor experiments are conducted to investigate whether there is any interaction between the drug and the drug, and between the drug and the excipient, so as to avoid the incompatibility problem during the formulation development process, and provide effective guidance for the subsequent formulation development work.