Talking about drug co-crystal technology - providing solutions for poorly soluble drugs

PART.
01 Overview Oral administration is a common, popular, painless and easy-to-operate mode of administration
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Among oral dosage forms, solid dosage forms are the most used
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The solid dosage form does not require a sterile environment during the production process, can be obtained in a relatively simple, low-cost, and high-efficiency process, and has high physicochemical stability
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As we all know, the dissolution rate is usually the rate-limiting step of solid dosage form drug absorption in the gastrointestinal tract, and the water solubility of the drug substance is a key parameter affecting the in vitro and in vivo quality of the preparation
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However, many drugs currently in use and in development are poorly water soluble
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Therefore, in order to obtain faster and more complete absorption properties, there are many methods to improve the solubility of these poorly soluble drugs
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Such as amorphous solid dispersions, micro and nano particles, salt formation, co-crystals, clathrates, liquid pellets,
etc.
Each of these methods has its own advantages and disadvantages
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On the other hand, there are few studies in the literature using co-crystal mixtures as a method to improve drug solubility because it is difficult to predict the solubility of co-crystals
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At present, the co-crystal system is still in the preliminary development stage in drug application
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PART.
02 HISTORICAL AND RECENT RESEARCH The first report on the use of eutectic mixtures to improve drug solubility and bioavailability began in 1961, when Sekiguchi and Obi discovered the formation of eutectic mixtures between sulfathiazole and urea
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Enhanced solubility of sulfathiazole was found upon dissolution of urea as a highly water-soluble carrier when the drug particles were exposed to the dissolution medium
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Since then, researches on cocrystals have been started one after another
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Since Sekiguchi and Obi reported the first co-crystal mixture, there has been relatively little research on co-crystals relative to other drug systems such as nanoparticles and amorphous solid dispersions
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As can be seen from the figure below, in the 80s and 90s, a large number of papers were devoted to improving the solubility of poorly soluble drugs using solid dispersion technology
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Figure 1.
Number of publications on the use of co-crystal technology since 1961.
However, since 2016, there has been a substantial increase in the number of publications involving the use of co-crystal mixtures to increase drug solubility
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In recent publications, other hydrophilic carriers have also been used, especially different types of organic acids such as adipic, succinic, ascorbic, fumaric and malonic acids, among others
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Table 1.
Solubility and Dissolution Rate Improvement of Co-crystal Mixtures The increased interest in drug co-crystals may be related to the following factors: (1) The preparation method is low cost, easy to manufacture and scale up; (2) The co-crystal is not considered new (3) In co-crystal systems, both components exist in crystalline form, which is highly stable compared to amorphous materials; (4) More and more research The advantages of using eutectic mixtures are highlighted, thereby attracting the attention of the pharmaceutical industry
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PART.
03 PHYSICAL CHEMICAL AND MICROSTRUCTURAL CHARACTERISTICS The main characteristic of eutectic mixtures is the simultaneous melting of the two components at a lower temperature.
Compared to the independent components, eutectic mixtures can be considered as intimate physical mixtures with high thermodynamic properties
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Thermodynamic parameters such as melting temperature Tm, melting enthalpy ΔHf and melting entropy ΔSf affect solubility
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The decrease in ΔHf of the eutectic mixture indicates a thermodynamically increased solubility of the eutectic mixture according to the Van't Hoff reaction
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PART.
04 Evaluation of Solubility and Dissolution Rate of Co-crystal Mixtures The improvement in water solubility of the drug after the formation of the co-crystal mixture is usually assessed by measuring the solubility, dissolution rate or intrinsic dissolution rate (IDR) of the co-crystal mixture
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The co-crystal mixture exhibited improved solubility and dissolution rate compared to individual drugs
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However, the mechanism of the increased solubility is currently not fully understood
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The chart below summarizes some of the main factors
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Figure 2.
The main factors for the solubility increase of the co-crystal mixture.
For the co-crystal mixture of sulfathiazole and urea, all the factors may be due to the use of a highly water-soluble carrier (urea), reduced drug particle size, and better wettability of drug crystals in the medium.
These factors all help to speed up the dissolution rate of sulfathiazole
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PART.
05 METHODS FOR THE PREPARATION OF THE eutectic mixture The first method to obtain the eutectic mixture is to melt the drug and the carrier at the same time, then cool until solidified, pulverize and sieve
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This technology requires mixing of the two components and heating above the maximum melting temperature of the two components, and due to the high temperature, it is necessary to consider whether the raw material will degrade at this temperature
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The second method is solvent evaporation, in which both components are dissolved in an organic solvent and evaporated using a rotary evaporator
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In addition to solvent evaporation methods, spray drying methods can also be used to prepare eutectic mixtures
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The main advantage of spray drying is the ease of scale-up
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Solvent evaporation, although common, has some disadvantages, such as the use of organic solvents
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Commercial production using this method requires a large amount of solvent, which will result in high production cost and time-consuming
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The type and rate of evaporation solvent can also have an effect on the microstructure of the product, potentially altering product properties
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The third method is mechanical methods, such as grinding, which are widely used to obtain eutectic mixtures
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The grinding method mainly induces eutectic formation by breaking and forming hydrogen bonds
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The fourth method is the liquid-assisted grinding method, which is also a commonly used method
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For example, use a mortar and pestle to grind the compound, then add a small amount of organic solvent as a catalyst or lubricant
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Grinding generates a certain amount of energy, which causes weak intermolecular interactions between the two components
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Compared with pure grinding, liquid-assisted grinding has the advantage of high efficiency
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Figure 3.
Main methods of preparation of eutectic mixtures PART.
06 Characterization of eutectic mixtures Characterization of eutectic mixtures remains a challenge, as lowering of the melting point of eutectic mixtures is the only indicator of eutectic formation
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The most widely used techniques are Differential Scanning Calorimetry (DSC), Powder X-ray Diffraction Analysis (PXRD), and Fourier Transform Infrared Spectroscopy (FTIR)
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Figure 4.
Solid state characterization of co-crystal mixtures PART.
07 Summary Co-crystal mixtures are suitable for increasing the solubility of poorly water-soluble oral drugs
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In addition, eutectic mixtures have other advantages
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For example, one of the main advantages of eutectic mixtures compared to amorphous solid dispersions is that both components are in crystalline form, which is more stable for manufacturing and storage
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Another advantage is that eutectic mixtures can be obtained by simple and low-cost methods and are easily scaled up
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However, the current study of the microstructure of eutectic mixtures is still a challenge and needs to be further explored
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It is believed that in the near future, our research on co-crystal mixtures will be more in-depth, and co-crystal technology will be better applied to pharmaceutical preparations
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References: [1] Bazzo GC , Pezzini BR , Stulzer HK .
Eutectic mixtures as an approach to enhance solubility, dissolution rate and oral bioavailability of poorly water-soluble drugs[J].
International Journal of Pharmaceutics, 588.