The Tao and Techniques of "Drug Co-Crystal"

Drug co-crystal means that the active drug molecule (API) and co-crystal former (CCF) crystallize in a fixed stoichiometric ratio in the same crystal lattice
.
Drug co-crystal is an emerging crystal form that has only been reported more in recent decades.
It has made APIs more diverse and can improve many physical and chemical properties of drugs.
In recent years, they have attracted more and more attention [1]
.
In general, drug co-crystal is a new solid form that can improve many physical and chemical properties of active drug ingredients.
Compared with single-component and compound drugs, it has certain advantages and is a potential new drug development technology
.
Figure 1 uses small squares instead of API, depicting its various forms of accumulation
.
This article will share novices from six parts: the formation principle of drug co-crystals, the preparation method of drug co-crystals, the difference between drug co-crystals and salts, the characterization methods of drug co-crystals, and the prospects of oral drug co-crystals and drug co-crystals that are on the market or under development.
Quick start "drug co-crystal"
.
PART 0 1.
The principle of drug co-crystal formation.
Tracing back to the essence of drug co-crystal, it is not difficult to find that it is actually a system automatically assembled by supramolecules, which is the result of the balance of kinetics, thermodynamics, and molecular recognition.
[3 ]
.
In this self-assembly process, the generation of supramolecular network of eutectic system will be greatly affected by steric effects and intermolecular interactions, which in turn affects the composition of crystals
.
In the drug eutectic system, the important interactions between molecules of different components include π-π stacking, van der Waals forces, halogen bonds and hydrogen bonds
.
Figure 2 shows some typical drug eutectic hydrogen bonds
.
In the study of eutectic, hydrogen bond is the most influential supramolecular force.
This is because it retains good directionality and saturation in the system, and most of the bonds are stronger after bonding
.
At present, most drug co-crystals are formed through hydrogen bonding, among which the more common hydrogen bonds include: OH···O, OH···N, NH···N and NH···O, etc.
These hydrogen The bond can be produced by the following synthons: carboxylic acid-pyridine, carboxylic acid-carboxylic acid, carboxylic acid-amide, amide-amide and alcohol-amine, etc..
PART 0 2.
Preparation methods of drug co-crystals The preparation methods of drug co-crystals are classified.
According to the morphology of the two components during synthesis, they can be divided into solid method and solution method [4]
.
Among them, the solid method means that both API and CCF are solid during the preparation process, mainly including grinding method and melting method, etc.
; while the solution method means that the two components are in a fluid state during the preparation process, with solvent evaporation, The reaction crystallization and suspension crystallization method and the like
.
Wang Lili et al.
[5] summarized it as shown in Figure 3 (based on the Web of Science database, the search title is cocrystal, the research direction is pharmacology pharmacy, and the time range is from January 2010 to March 2020.
More than 170 documents were retrieved.
More than 100 articles involving preparation methods)
.
The advantages and disadvantages of different eutectic preparation methods are summarized in Table 1
.
PART 0 3.
The difference between drug co-crystal and salt Figure 4 classifies the solid form of API
.
According to the FDA's "Guidelines for the Regulatory Classification of Co-crystals of Drugs (2018)", co-crystals refer to crystalline materials formed by combining two or more different molecules in the same crystal lattice through non-ionic and non-covalent bonds in a fixed stoichiometric ratio.
, And the salt is a crystalline compound formed by the substitution of a part or all of the acidic hydrogen by a metal or metalloid group
.
From a regulatory perspective, co-crystals do not need to register new active substances or chemical entities, while in the case of pharmaceutical salts, new active substances or chemical entities need to be registered
.
In the process of drug development, it is necessary to carefully consider the performance parameters of the drug and the requirements for clinical use, and select the best solid form accordingly
.
This is because the different solid forms of APIs, such as drug polymorphs, salts, amorphous and eutectic, will cause large differences in their physical and chemical properties, which will have a profound impact on the efficacy and pharmacological and toxicological effects. .
PART 0 4.
Characterization method of drug co-crystal Characterization is a key step.
After the drug co-crystal is obtained, it should be characterized to distinguish the difference between the co-crystal and API, and determine its crystal phase and chemical purity
.
Commonly used characterization methods [6] include single crystal X-ray diffraction (SXRD), powder X-ray diffraction (PXRD), infrared spectroscopy (IR), Raman spectroscopy (RM), thermogravimetry (TGA), differential scanning calorimetry method (DSC), solid-state nuclear magnetic resonance (ssNMR), scanning electron microscopy (SEM), and the like
.
SXRD [7] is the most accurate and authoritative method for identifying the state of drug eutectic substances.
It is an absolute crystal type identification method and the "gold standard" for crystal structure characterization
.
SXRD can determine the spatial arrangement, structural symmetry and interaction force of atoms (molecules, ions) inside the eutectic structure, and realize the identification of the drug eutectic substance state
.
PXRD takes countless powder crystal material samples as the research object, and analyzes many tiny particle samples together
.
The PXRD patterns of crystalline and amorphous materials show sharp fronts and dispersion peaks, respectively
.
Usually the formation of eutectic is accompanied by the disappearance of all or part of the characteristic peaks of each raw material component and the appearance of new peaks.
Therefore, the use of PXRD can quickly realize the identification of the eutectic crystal phase and the detection of the purity of the crystal phase
.
It is worth noting that in the process of co-crystal screening, the appearance of new powder diffraction peaks does not necessarily mean the formation of co-crystals.
It is also necessary to pay attention to the polymorphic form of the drug substance itself.
It may be that the drug substance has undergone crystal transformation
.
Thermal analysis methods mainly include TGA and DSC, which measure the relationship between the physical and chemical properties of drug co-crystals with temperature changes under program control temperature, and study the crystal form transformation, melting and other physical changes and dehydration of drug co-crystals during heating.
Chemical changes such as oxidation and observation of the phase transition process can be used as a method for eutectic identification and purity inspection
.
When the drug co-crystal contains volatile components, TGA technology is particularly useful because it can determine the stoichiometry of volatile components through weight loss, and is suitable for crystalline substances containing different amounts and types of crystalline solvents (or water) in the test product.
Identification of
.
DSC uses the unique thermodynamic properties of different crystalline materials to identify the number and position of endothermic peaks or exothermic peaks
.
IR can use the difference of the position and intensity of the infrared spectrum absorption peak of different crystal material molecules in a certain wave number range to realize the identification of the crystal material state
.
It is usually recommended to use the attenuated total reflection method to avoid the phenomenon of crystal conversion that may be caused by grinding and pressing during sample preparation
.
SEM can observe the original three-dimensional morphology of the sample while analyzing the composition of the small area of ​​the sample, and use the signal excited by the focused electron beam to scan the surface of the solid sample for imaging
.
NMR technology is divided into liquid and solid according to the research object.
The hydrogen spectrum (1H-NMR) and carbon spectrum (13C-NMR) are the most widely used
.
Liquid NMR is widely used to characterize the microstructure and dynamics of substances in solution, and obtain information such as chemical structure and spatial conformation
.
Solid-state NMR (ssNMR) takes solid samples as the research object, and realizes high-resolution and rapid detection of solid samples through the combination of magic angle rotation and cross-polarization techniques
.
PART 0 5.
Oral drug co-crystals that are on the market or under research Feng Yumiao [8] summarized that in the past 20 years, it has developed from pre-clinical research to product approval for marketing.
See the table for details of some oral co-crystals 2
.
In recent years, drug co-crystals have found a way to get approved drugs from pre-clinical research
.
For example, the drug co-crystal product sacubatril and valsartan sodium tablets (Entresto, Entresto) was approved by the U.
S.
FDA for the treatment of chronic heart failure in January 2015, and entered the blockbuster drug ranks in 2018.
, Global sales reached 1.
028 billion U.
S.
dollars
.
Compared with the two single-component drugs that make up the drug and other traditional drugs, Entresto has shown a better effect in the treatment of heart failure, achieving a synergistic effect of one plus one greater than two, resulting in a 20% reduction in cardiovascular deaths , Has become the drug of choice for the treatment of heart failure[9.
10]
.
Tramadol hydrochloride-celecoxib co-crystal (Esteve) developed by Mundipharma Research Limited Lab has entered the Chinese market as a class I innovative drug (acceptance number: JXHL1700131)
.
In clinical trials, compared with tramadol hydrochloride, celecoxib and the combination of the two, the pharmacokinetic parameters of the API in the tramadol hydrochloride-celecoxib co-crystal has been improved, which can not only effectively reduce The maximum concentration, side effects and addiction of tramadol hydrochloride can also increase the maximum blood concentration of celecoxib, increase the analgesic effect of celecoxib, and effectively relieve pain [11.
12]
.
The launch of drug co-crystal products provides a new idea for the development of new drugs, which is expected to alleviate the current time-consuming and laborious development of new drugs and become a viable substitute for traditional drugs
.
PART 0 6.
Prospects of drug co-crystals The research and development of drug co-crystals is not only to improve the physical and chemical properties of APIs, but more importantly, to use co-crystals as a new drug combination method to increase the value of drug combination to a greater extent
.
Although the research on drug co-crystals has increased substantially in recent years, most of them have stayed at the analysis of co-crystal structure, and the related mechanisms of metabolism in the body are rarely involved
.
How to design co-crystal drugs, develop new values ​​of old drugs, and how co-crystal drugs meet the requirements of the pharmacopoeia and laws, etc.
, and more research data on co-crystals are needed to support
.
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Pharmaceutical cocrystals: A review of preparations, physicochemical properties and applications[J].
Acta Pharm Sin B, 2021, 11(8):2537-2564.
[ 2] Zhang Xiaoming.
Synthesis, characterization and properties of drug co-crystals[D].
Jilin University, 2016.
[3] Niu Huihui.
Design, synthesis, characterization and properties of several drug co-crystals[D].
Northwest Normal University, 2021 .
[4] KARIMI-JAFARI M, PADRELA L, WALKER GM, et al.
Creating cocrystals: a review of pharmaceutical cocrystal preparation routes and ppplications[J].
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Growth Des.
, 2018, 18(10):6370-6387 [5] Wang Lili, Gao Ziyao, Liu Shuyu.
New progress in the study of drug co-crystals[J].
Chinese Journal of Pharmaceutical Industry, 2021, 52(07):881-890.
[6] Xiong Jing, Dai Xialin, He Lan, et al.
Research progress of drug co-crystal characterization methods[J].
Chinese Pharmacovigilance:1-13.
[7] BOUBAKRI R, SZYBOWICZ M, SADEJ M, et al.
Synthesis, single crystal structural investigation, Hirshfeld surface analysis,