Consideration Of Polymorphic Forms Of Raw Materials And Preparations In Drug Development

With the deepening of drug research and development, the proportion of insoluble drugs in drug research and development is constantly increasing, and the problem of crystal form is becoming more and more prominent. Different crystal forms of drugs may affect their dissolution and release in vivo, which may affect the clinical efficacy and safety of the drug to a certain extent.

For polymorphic drugs, when developing solid oral preparations, research on the crystal form will help us choose a stable and controllable crystal form for clinical use.

Part 1 What Is The Crystal Phenomenon

Solid matter can consist of crystalline and amorphous matter. Crystalline substances are due to the orderly arrangement of molecules, atoms, and ions that make up the substance in three-dimensional space, with a periodic arrangement. Amorphous substances refer to the disordered accumulation of molecules, atoms, and ions in three-dimensional space. Crystalline substances are also called crystals. When the determination of the crystal structure finds that there are solvents or water molecules in the sample molecules, the possibility of polymorphism in the sample crystals will increase, because the sample molecules are easy to form with solvents or water molecules. Hydrogen bonds, when the molecules of the tested sample are combined with different solvent molecules, substances of different crystal forms will be formed.

Solvent-free crystals may also have polymorphism due to the different symmetrical arrangement of molecules. Therefore, crystal form is an important physical and chemical property of a compound. For polymorphic drugs, some physical and chemical properties (such as melting point, solubility, stability) may be different due to different crystal structures; and under different conditions, each crystal of the same compound There may be mutual conversion between types. For example, there are four crystal forms of rifampicin, an anti-tuberculosis drug widely reported in the literature: four types including type I, type II, type SV, and amorphous. The study found that the physical and chemical properties and bioavailability of rifampicin are closely related to its crystal form; among them, type I and type II are effective crystal forms, and the dissolution rates of the two are basically the same, but the human bioavailability of type I is better than that of type II.

Part 2 What Should Be Considered In The Crystal Form Research Of Raw Materials?

1.For poorly soluble solid drugs, when developing as solid oral preparations, the crystal form of the raw drug should be studied. Because the same compound may produce different crystal forms due to differences in the preparation process (such as using different solvents for recrystallization or different crystallization methods).

2. The change of the crystal form of a compound is not only determined by its own properties, but also affected by other factors. For example, under different conditions of temperature, light, and humidity, the crystal form of the compound will change with water loss or water absorption; different solvents will also have different effects on the crystal form of the compound.

For brand-new drugs, it is first necessary to study whether there is polymorphism, consider various factors that may affect the crystal form (temperature, recrystallization solvent, and recrystallization conditions), and design different recrystallization schemes. Commonly used solvents should be considered when selecting a recrystallization solvent. The selection range should consider single solvent systems such as polar solvents, medium polar solvents, and non-polar solvents; on the basis of single solvent systems, mixed solvents and their differences should also be used. ratio for research. At the same time, the effect of temperature change on the crystal form should also be studied. Usually, according to the characteristics of the sample, it is advisable to design the temperature of the recrystallization experiment at a low temperature of 5°C and a normal temperature of 20°C. Observe the changes in the shape of the sample crystals under different temperature environments, and obtain crystal samples under various recrystallization experimental conditions.

After determining whether the compound has polymorphism, the process of each crystal form should be further operated to ensure the stability of the crystallization conditions in the preparation process. And the target crystal form of the compound should be used for subsequent pharmacology, toxicology and clinical trials; if the results of later pharmacology, toxicology and clinical trials show that the bioavailability of the selected crystal form is not good, and the effective therapeutic concentration cannot be reached, further studies are required. Further crystal form studies.

3. If developing and developing existing national standard drugs and drugs that have been marketed abroad, the developer must first conduct a full research on the literature, obtain information about polymorphism, and compare the self-produced product with the marketed product (or its literature value) ) physical and chemical properties (melting point, IR, DSC, d and I/Io values in the powder X-ray diffraction pattern), to ensure that the crystal form of the self-made product is consistent with the crystal form of the imitated product.

If the relevant reference materials cannot be obtained, or if it is not clear about the crystal form of the product on the market and whether there is a selectivity of the crystal form (that is, whether the drug has different physical and chemical properties and bioavailability in different crystal forms), it is generally possible to suspend the Consider the problem of crystal form; however, its preparation process should be fixed to ensure that the crystal form of the self-made product is stable and consistent. Different drugs have different crystal forms, and developers should conduct research on crystal forms in a targeted manner.

4. For drugs with polymorphism but no crystal form selectivity, it is generally not necessary to conduct quality research on the crystal form. For drugs with polymorphism and crystal form selectivity, quality research on crystal forms should be carried out, and crystal form identification or purity inspection items should be added to the quality standards. At present, the crystal form inspection mainly includes methods such as melting point, IR, DSC, powder X-ray diffraction, polarized light microscope, and electron microscope.

For different crystal forms of different drugs, the specificity of the inspection method is different. For example, there is no difference in the melting point or IR between different crystal forms of some drugs, and the crystal forms of some drugs need to be compared through X-ray diffraction tests; while the crystal forms of some compounds can be identified only from the melting point. Therefore, when we conduct crystal quality research, we must first select an appropriate and specific crystal form inspection method based on the characteristics of the compound itself, and formulate a reasonable limit based on the test results to control the content of effective crystal forms or invalid crystal forms. , to ensure the consistency of the sample crystal form between batches. For drugs with crystal form selectivity, crystal form inspection indicators should also be set in the stability test to fully reflect changes in sample quality, and appropriate storage conditions should be determined based on test results to ensure crystal form stability.

According to the research results of the crystal form in the synthesis process and stability research, formulate scientific and feasible inspection items in the quality standard to ensure the quality of the sample. For the imitation of drugs whose marketed crystal form and crystal form selectivity are not yet clear, if the clinical research results of the self-made product show that the treatment is not equivalent or biologically not equivalent. After excluding the influence of other factors, the influence of the crystal form should be considered, and the developer should return to conduct research on the crystal form to ensure that the self-made product is therapeutically equivalent or bioequivalent to the marketed product.

Part 3 Preparation Crystal Form Research, What Should Be Paid Attention To!

After the crystal form of the drug substance has been fully understood and necessary controls have been carried out, it should also be considered that the crystal form may change due to the preparation process and excipients during the preparation process. Because from the raw material of the drug to the finished solid preparation, a multi-step process is required, and these processes may change the crystal form of the drug. For example:

(1) The study found that the pulverization process in the preparation process can change the drug from a stable crystal form to an amorphous form, or change a metastable form into a stable form or an amorphous form. This is mainly due to the increase in temperature caused by mechanical action, which makes the drug The crystal form of the drug has changed.

(2) In the preparation process of solid preparations, granulation is usually an essential one-step process, and water and alcoholic aqueous solutions are the most commonly used binders. Granulation with a binder often results in a change in the crystalline form of the drug.

(3) The drying process in the process will also affect the crystal form of the drug, because polymorphic drugs will also undergo crystal transformation at high temperatures.

From the research materials currently declared, it is found that research units have done little research on the crystal form of the preparation process, which is mainly due to the addition of a large number of excipients in the preparation, which brings certain difficulties to the identification of the crystal form of the raw material drug in the drug. Difficulties. The usual solution is to simulate the preparation process. You can add no excipients or increase the amount of raw materials in a certain proportion to make pharmaceutical preparation samples with a certain amount of excipients but different contents of raw materials, and then use appropriate methods to test the crystal form. Research.

If it is found that the crystal form has changed during the preparation process, other appropriate methods should be considered for preparation; avoid changes in the crystal form during the preparation process that will affect the dissolution and absorption of the drug in the body. In short, by understanding and analyzing the influence of various factors in the processing of solid preparations on polymorphic drugs, for drugs with polymorphic forms and large differences in efficacy between different crystalline forms, first of all, in the process of prescription and process screening must Research and clarify the possible influence of various factors on the crystal form.

Investigate the crystal form changes of the main drug before and after the process, select the process conditions suitable for the crystal form of this product, and formulate corresponding operating specifications and detection methods. At the same time, the crystal form should also be investigated in the stability study, and the long-term reserved samples should be compared before and after the test, and the reasonable storage conditions and validity period of the drug should be determined according to the change of the crystal form. Through the above work, minimize the generation of low-efficiency and invalid crystal forms; avoid the difference in dissolution rate and solubility of different crystal forms of the same drug, which will affect the bioavailability or effectiveness of treatment, and ensure the safety of drug use and effectiveness.