The Value and Importance of Preformulation Research

Importance of Preformulation Studies

    Preformulation studies has gradually become a routine research project in the design and improvement of dosage forms and preparations, which provides a basis for further design of dosage forms and optimization of the formulation process of preparations.

    PharmaceuticaI prefomulation studies refer to the understanding, analysis, utilization or improvement of a series of basic physical, chemical and formulation properties of a drug before designing a formulation. Its purpose is to make the drug stable and effective, and to meet the requirements of formulation prescription and formulation process in industrial production. The basic physical and chemical properties of drugs include chemical structure, melting point, crystal form, solubility, dissolution rate, partition coefficient, acidity, alkalinity, salt type and spectral characteristics; the preparation properties of drugs include particle size, crystal shape, crystallinity, purity, moisture absorption properties, fluidity, compressibility, and interactions with excipients. Some of these properties can be directly obtained from the chemical synthesis stage of the drug, such as the chemical structure of the drug, melting point, infrared absorption spectrum and ultraviolet absorption spectrum, purity, etc.; Relevant data, such as drug dissolution rate and solubility, crystal form, etc. Pre-formulation research is the foundation of formulation development and it requires Preparers have certain ability to collect data, engage in scientific research and analyze experimental results. For different drug dosage forms, the formulator should have a full understanding of the characteristics of the dosage form, so as to be able to selectively understand and study the relevant properties of the drug. For example, for an oral solid dosage form of a poorly soluble drug, solubility, dissolution rate and crystal form may be one of the most important properties; while for a solution injection, in addition to solubility, the stability of the drug and its analytical methods are all required important content. Pre-prescribing research is generally conducted after the source of the drug, the pharmacology and pharmacodynamics of the drug, and the object to be treated and the therapeutic dose are known. Therefore, an experienced preparer can determine the research content on the basis of the existing data.

Purpose and Importance of Preformulation Studies

    The purpose of the pre-formulation research is to provide the basis for the design of the formulation process, and to provide a mechanism-specific and targeted solution to the problems arising in the formulation process research.

The quality characteristics of the finished drug product are largely determined by the properties of the drug substance: although there are many means to improve the quality characteristics and process reliability of the drug product, they are often not as effective as controlling the properties of the drug substance. ;

    The trend of modern product development is to move the control point forward;

In the QbD research and development requirements, another important purpose of pre-prescription research is to provide the basis for preliminary risk assessment for preparation research, and to determine the direction and scope of preparation research;

The purpose of preformulation studies 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.

Medicilon has been offering high quality analytical testing services to the pharmaceutical industry for decades. We offer a wide range of quality control testing services to support drug research, registration and production. Biopharmaceutical companies also use many of the same services and Medicilon has also added new services to accommodate their unique needs (detailed in the following).

Preformulation Studies

    We offer a full spectrum of Pharmaceutical Preformulation testing capabilities, including:

• 1. Solubility Studies

• 2. pH Stability Studies

• 3. Particle Size Analysis

• 4. Powder Flow Testing

• 5. Polymorphism Studies

• 6. Structural Identification

• 7. Forced Degradation Studies

• 8. Microstructural Analysis

• 9. Unknown Compound Identification

• 10. Analytical R&D

• 11. Technical Consulting

    Preformulation: A stage of development during which the physicochemical properties of drug substance are characterized.

Some commonly evaluated parameters:

• 1. Solubility

• 2. Dissolution Behavior

• 3. Stability

• 4. Partition Coefficient

• 5. Ionization Constant (pKa)

• 6. Solid State Properties such as crystal forms/polymorphs, water sorption behavior, surface properties, particle size and shape and other mechanical properties, et. al.

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 API

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.

5. API’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.

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