Scientific thinking on crystal control in application of new drugs

Source: the full name of Anda in the preface of Yaodu Jingwei 2017-12-05 is abbreviated new drug application The main difference between "short new drug anda" and "brand new drug NDA" is that NDA needs to provide preclinical data (such as animal test data) and clinical data; anda does not need to submit this research repeatedly, but instead is bioequivalence test, that is to say, it needs to prove that the active ingredients used are safe and effective, and the drug has the same absorption speed and absorption process as rld after entering the human body Degree, and finally achieve the goal of the same effect See Figure 1 below: Figure 1: comparison of data required by NDA and anda In addition to bioequivalence data, the declaration data of Anda applicants also need to have pharmaceutical equivalence data consistent with rld The premise of pharmaceutical equivalence is that it needs to have "the same" active ingredients as rld Although many anda and rld seem to have the same active ingredients, many of them have multiple crystal structures, i.e polycrystalline phenomenon Therefore, in essence, they may not have the "same" active ingredients as rld The existence of drug polycrystal may lead to the difference of some physical and chemical properties of active ingredients, and even produce different bioavailability, which can not meet the requirements of bioequivalence, and ultimately can not achieve the purpose of treatment equivalence Polymorphisms of drugs and their effects As a kind of substance with pharmacological action, the arrangement of molecules inside the same substance as other substances will change When the arrangement number, position and lattice form of drug molecules in each crystal form are different, different crystal structures will be formed, so that the crystal of the same drug has two or more spatial structures and crystal cell constants, which is called drug polymorphism (pol ymorphism)。 Solvate is a special crystal form, also known as pseudopolycrystal It is a crystal substance formed by the combination of compound molecules and one or more solvent molecules in a certain form If the solvent contained in the molecule is water, the solvate is also known as hydrate For polycrystals, due to their different internal structures, they will have different physical and chemical properties, such as thermodynamics, dynamics, mechanical properties, and sometimes the differences of these properties just can affect the feasibility of API production, the feasibility of finished product production, and even rise to product quality problems, such as stability, dissolution, bioavailability Unpredictable crystal formation sometimes leads to serious commercial consequences: ritonavir, an anti AIDS drug, was found by Abbott pharmaceutical company in 1992 and successfully listed in 1996; however, in 1998, it was found that a more stable type II product appeared in the market Type II is more thermodynamically stable than the original crystal (type I), but its solubility is more than crystal Type I is poor, which greatly affects the dissolution rate and bioavailability of the preparation, resulting in the withdrawal of this marketed preparation product from the market; Abbott has to re study it to re market However, the direct economic loss of this product after delisting and re listing is at least 250 million US dollars 1 Influence on solubility, dissolution and BA / be when the state of crystalline substances of drugs is different, the solubility of crystalline drugs or the dissolution properties of solid preparations may be significantly different; if the difference is too large, it may be reflected in the bioavailability For example, carbamazepine, the bioavailability of crystal type I was significantly higher than that of crystal type II In fact, whether the difference in solubility of drugs with different crystal types will be reflected in the BA / be of products depends on the absorption rate and degree of drugs in vivo, including the peristalsis of gastrointestinal tract and the permeability of small intestine At this time, the BCS classification we often say plays a role: if the absorption rate and degree of a drug are affected by the dissolution rate, then the absorption rate and degree of different crystal types will be affected However, if the absorption speed and degree of a drug are only affected by the permeability of the small intestine, the difference of solubility between different crystal forms may not be reflected in the difference of Ba / be Therefore, if the different crystal forms of the drug have the characteristics of high solubility and fast dissolution relative to the gastric emptying speed, the solubility difference of different crystal forms does not seem to have an effect on BA / be in the end Therefore, for generic drugs, the later dissolution test can be used to distinguish the quality difference between batches, because sometimes the inadvertent change of crystal form may be reflected in the dissolution curve 2 Different crystal types may have different physical and mechanical properties, such as hygroscopicity, particle shape, density, fluidity and compressibility, which may ultimately reflect on the feasibility of the production of APIs and finished preparations, as well as the reproducibility of production The influence of different crystal types on the production sometimes depends on the formulation and production process of the preparation For example, for the products of the direct pressing process, the solid form of the drug plays a very important role in the production process; for the products of the wet granulating process, the solid form of the drug can be weakened to a certain extent, and the influence on the production process has no key role Therefore, whether the drug crystal has an impact on the production of drugs mainly depends on whether the qualified products consistent with the quality standards can be produced in the process of process validation 3 The influence on stability the difference of different crystal forms sometimes has different physical and chemical properties due to different thermodynamic stability, so many drug research and development will give priority to the stable crystal form, because the possibility of the stable crystal form to other crystal forms is the least However, if there is polymorphism in solid drugs and their preparations, the material state of "dominant drug crystal" should be used as the pharmaceutical crystal of drug raw materials and their preparations to ensure the clinical effectiveness, safety and quality controllability of drugs The so-called "dominant drug crystal" refers to one or more crystal types of a solid chemical drug are most suitable for the preparation of drugs suitable for clinical application as drug raw materials, and can meet the stability of drug use requirements, but not necessarily the most stable crystal For reasons of chemical stability, anda applicants need to prove that their products are stable enough before obtaining anda approval Different crystal forms may have different chemical stability problems, so it is necessary to pay more attention to whether the crystal form changes during the whole drug development process However, the change of drug crystal is the result of many factors, such as prescription factor, production process factor and packaging factor In addition, it is the stability of the finished product, not the stability of the drug substance that affects the drug quality That is to say, for the drug substance with unstable crystal, if it can ensure that the finished product is stable and will not affect the product quality, it is also possible to To accept For polycrystalline drugs, some production processes sometimes lead to phase transformation, such as drying, whole grain, micronization, wet granulation, spray drying, and pressing At the same time, the change of environmental humidity and temperature will sometimes cause phase transition Therefore, in order to prevent the occurrence of these potential phase transitions, the most stable crystal form is generally preferred, and the crystal form monitoring of the whole production process should be paid attention to The application of solid drug polymorphic form and its "identity" anda shall contain relevant data to prove that it has pharmaceutical equivalence with rld; pharmaceutical equivalence means that anda and rld need to have "the same" active ingredients, and at the same time, the specification, dosage form and administration mode shall be consistent with rld So, here is a question: for drugs with multiple crystal types, do they have "the same" with each other? For material scientists who focus on solid properties, drugs with different crystal types do not have the same identity; but for regulators who focus on the structure of compounds, the safety and effectiveness of drugs, drugs with different crystal types have the same identity In their eyes, different crystal types of drugs are "the same" Therefore, for anda applicants, the regulations do not require that the active ingredients of Anda applicants and rld have the same crystal characteristics Although different crystal forms may make raw materials have different characteristics, sometimes even affect the quality attributes of products; however, there are other factors that may affect the quality attributes of products, such as differences in drug absorption rate and absorption degree, prescription composition and proportion, production process, physical and chemical properties of raw materials and excipients, etc., which may offset the crystal form difference band The negative effect of the coming Therefore, the producibility, bioequivalence and stability of Anda can not be doubted even if the crystal form of the used API is inconsistent with rld As long as the generic product has bioequivalence and appropriate robustness with rld, and can be produced under the condition of cGMPs, it is not necessarily the same crystal form with rld Up to now, FDA has approved many products with different crystal forms from rld, such as warfarin sodium, famotidine and ranitidine; FDA has also approved products with different solvates or hydrates from the active ingredients used in rld, such as terazosin, ampicillin and cefadroxil In these cases, no safety and effectiveness incidents occurred Therefore, the "same" active ingredient in the generic application only refers to the same chemical structure, and does not involve the same crystal form or not; as long as it is reasonable, the crystal form can be different Crystal monitoring in generic drugs is very important to understand the crystal form of APIs, because it can ensure that our prescriptions and processes can be controlled to meet the required quality standards and attributes In general, we can learn from scientific literature, patents, pharmacopoeia or other ways whether the drug substance has the characteristics of polymorphism or intergranular However, sometimes due to the lack of public data or the crystal shape has a great impact on product quality, we need to screen the crystal shape, and if necessary, we can draw up relevant test indicators to indirectly control the crystal shape 1 For API with high solubility Figure 2: according to the solubility of API, it is necessary to make relevant standards to control the crystal form The decision tree in Figure 2 is a scheme to determine whether to set a standard control for crystal form It can be seen from Figure 2 that if all the related crystal forms have no significant difference in solubility or have high solubility, then it can be considered that the polymorph of the drug has no significant impact on bioavailability, so it is not necessary to establish a crystal form standard for the drug substance or finished product The related crystallographic forms in the figure refer to the crystallographic forms that will appear in the production of APIs, the production and storage of finished preparations, which should be considered in the scope; while the crystallographic forms that are not likely to appear may not be considered For example, the solvent in a solvate will not be used at all in the production process, so the crystal form of the solvate is not relevant polymers, and the influence of the crystal form does not need to be considered in the actual R & D and production 2 For low solubility APIs, if there is at least one crystal form with poor solubility (based on BCS classification), then we need to control its relevant quality indicators: Figure 3: for crystal type with poor solubility, we need to establish relevant standard control