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;
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.
SOLID‑STATE PROPERTIES
m.p., pKa, logD
POLYMORPHS
SOLUBILITY AND PERMEABILITY
WATER CONTENT (hygroscopicity)
CHEMICAL AND PHYSICAL STABILITY
PARTICLE SIZE, SURFACE AREA, AND DENSITY
MECHANICAL PROPERTIES:
PLASTICITY, ELASTICITY,
COMPRESSIBILITY, FLOWABILITY
The items under investigation need to consider the general properties and properties related to the raw materials and preparations.
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 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.
Structural differences in the physical state of common solids
Degree of structural order: most stable crystalline = metastable crystalline>liquid crystal>amorphous
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. 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 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
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.
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 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.
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.
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.
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 pH-solubility Solubility in dissolution mediumGeneral conclusions on crystal form changes
Regulatory requirements for crystal form
changes
Current regulations require changes in the
physical state of APIs
Treatment of crystal form changes in
generic drugs
Case of metastable crystal form change
Frequently asked questions about crystal forms in pre-formulations
How to determine the crystal form used in
the original research:
How to check the stability of the crystal
form in the preparation?
Solubility
Four types of solubility information:
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