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Pre-formulation Study of Generic Drug Formulations

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The purpose and importance of pre-prescription research

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


    The quality characteristics of the final product are largely determined by the nature of the drug substance: Although there are many methods to improve the quality characteristics and process reliability of the drug product, the effectiveness of these methods is often not as good as the control of the characteristics 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-formulation research is to provide a basis for preliminary risk assessment for formulation research, and to determine the direction and scope of formulation research;

Main content of  pre-formulation research

The main content of  pre-formulation research is to figure out the physical, chemical, biological, and mechanical properties of APIs and excipients.

    Physical properties of raw materials: solubility, crystal form, particle size, crystal habit, etc.

    Chemical properties of raw materials: stability, compatibility of excipients, etc.

    Biological properties of APIs: permeability, BCS classification, stability of enzyme metabolism

    The mechanical properties of the API: fluidity, compressibility (plasticity and elasticity), density, etc.

Pre-formulation research also needs to be combined with formulation research to determine the key attributes of APIs CQA: The impact of API properties on formulations is not only the work of formulation research, but also the work of  pre-formulation research.

The physical and chemical properties of the raw materials declared by the general NDA


    m.p., pKa, logD



    WATER CONTENT (hygroscopicity)






The items under investigation need to consider the general properties and properties related to the raw materials and preparations.

Selection of crystal forms of generic drugs: understanding the principle of selection of crystal forms (physical states) of original drugs

    Under normal circumstances, the original drug has been screened for crystal form.

    The basic purpose of the polymorphic screening of the original research drug is to determine and select the most stable crystal form to reduce the risk of mutation of the crystal form, not to improve the properties of the API;

    Crystallization is better than amorphous. The thermodynamically most stable crystal form is better than the metastable crystal form. The lower the potential energy state, the more stable; the high potential energy state has a tendency to transform into the low potential energy state, although the kinetic rate may be slow.

    The choice of amorphous is generally only in two cases: the raw material cannot be found in a crystalline state or the bioavailability is too low and there is no other better way to improve it;

    The choice between hydrate and anhydrate mainly depends on which one is more stable and interconvertible under drug storage conditions;

    Balance and trade-offs are hard to avoid; sometimes one has to choose a physical state that is not commonly used or is not stable enough.

The physical and chemical properties of raw materials are affected by their physical state

Structural differences in the physical state of common solids

Structural differences

Degree of structural order: most stable crystalline = metastable crystalline>liquid crystal>amorphous

Energy difference of common solid physical state

    Energy (free energy) difference: the most stable crystal

    The difference in energy determines the solubility and stability of the physical state: the higher the potential energy, the higher the solubility and the worse the stability.

Stability: The state of high free energy will spontaneously transform into the state of low free energy, but the kinetic rate is fast or slow.

General conclusions on crystal form changes

It can be seen from the above introduction:

    Different physical forms are not completely equivalent but can be freely interchanged;

    The impact of physical form changes on the quality of medicines is not certain and needs to be specifically evaluated

Regulatory requirements for crystal form changes

The existing guiding principles include:

    Guidance for Industry, ANDAs: Pharmaceutical Solid Polymorphism; July 2007;

     ICH Q6A Guideline;

    Guidance for Industry, Regulatory Classification of Pharmaceutical Co-Crystals, Apr 2013

Current regulations require changes in the physical state of APIs

    The guiding principles retain the flexibility to adopt any physical state in generic drugs, including metastable and amorphous;

    For generic drugs, the FDA ANDA guidelines propose that changes in physical form need to evaluate three possible effects: on solubility, dissolution, and bioavailability; on product production technology; and on stability;

    The requirement for stability is the stability of product quality, but does not directly require the physical state to be stable (state stability may be a requirement of intellectual property), and it is not encouraged to monitor the physical state of the API in the formulation;

    When applying for ANDA, in addition to the above-mentioned guideline on crystal form, it is also necessary to consider that the change of crystal form must comply with other guiding principles, such as the FDA’s guiding principles on the shape and size of generic drugs and the breaking of tablets.

Treatment of crystal form changes in generic drugs

    In the case of the original crystal form without patent protection, the generic drug should use the original crystal form as much as possible, and try to avoid the metastable crystal form;

    Amorphous crystals tend to be larger than metastable crystals, but they are more predictable;

    The presence of water will greatly accelerate the rate of amorphous crystallization;

    If changes are considered, three possible impacts need to be assessed:

    Solubility, dissolution and bioavailability: The change of drugs with greater solubility may have little effect; BCSII and class IV drugs with lower solubility are generally more difficult to change.

    Stability: If the stability of the API is not good, and the limits of impurities, especially genotoxic impurities, are very strict, it is necessary to carefully evaluate their possible effects.

    Product production process: Generally, the process can be adjusted to solve the problem.

      In addition, other requirements regarding generic drugs need to be considered.

Case of metastable crystal form change

Case 1: Decreased stability and excessive impurities;

Case 2: Density decreased, causing the tablet size to exceed the requirements of the FDA guidelines. Special attention should be paid to products with high drug loading.

Frequently asked questions about crystal forms in pre-formulations

How to determine the crystal form used in the original research:

    Grasp the idea of crystal form selection of the original research: usually the original research must use the most stable crystal form. If there is crystallization, it will not use the amorphous form, unless it is for reasons of increasing solubility;

    Patent and public documents generally reveal the original crystal form or whether there is a special reason for adopting the non-most stable state;

    If there is no clear crystal form in the literature, the most reliable thing is to screen and evaluate the crystal form to determine the most stable crystal form;

    Direct inspection of the crystal form of the original developed agent is only feasible when part of the drug loading is high, and it is necessary to make sure that the excipients have no interference, so the reliability is limited.

How to check the stability of the crystal form in the preparation?

    The regulations do not require that the crystal form in the preparation must be stable, and in general, it is not encouraged to directly check the stability of the crystal form in the preparation;

    Generally, it is replaced by checking the quality index of the preparation, especially the stability of the index related to the crystal form (surrogate test);

    If necessary, it can be replaced by the crystal form stability of the API under the preparation process and storage conditions: the influence of solid preparation excipients on the crystal form transformation of API is quite rare;

    When the non-most stable crystal form is intentionally used in the preparation and the crystal form transformation has an impact on the quality index of the preparation, it is beneficial to directly check the stability of the crystal form in the preparation, but it is not necessary.


Four types of solubility information:

    pH-solubility: reference for formulation process development

    Solubility in solvents: reference for the development of APIs and preparations

    Solubility in dissolution media: a reference for dissolution method development

    Solubility in bio-related media: SGF, SIF, etc. Evaluation of biopharmaceutical classification reference


Solubility in dissolution medium

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Preformulation research

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Steps in Generic Drug Development

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