Cocrystallization of Active Pharmaceutical Ingredients Derived from Traditional Chinese Medicines

Abstract

This review highlights the cocrystals of active pharmaceutical ingredients (APIs) derived from traditional Chinese medicines (TCMs) in categories, ∆pK_a rule, preparation, characterization, and physicochemical properties, reported in 113 literature reports. It is founded that the formation of all of the cocrystals is in accordance with ∆pK_a rule. Three preparation methods such as evaporation cocrystallization, grinding method, and suspension method, are used most, accounting for 44, 27, and 16%, respectively. Almost all cocrystals are characterized by powder X-ray diffraction (PXRD). Thermal analysis techniques are used for 81% of cocrystals, and more than half of cocrystals are characterized by IR. Forty-four percent of cocrystals are determined by single crystal X-ray diffraction (SXRD) since it is difficult to get the single crystals of cocrystals. Most cocrystals of APIs in TCMs exhibit 1–10 folds enhancement in solubility, dissolution, dissolution rate, and bioavailability, and a few of them are increased by dozens or even hundreds of times in these properties. This review provides a meaningful reference for more and more APIs in TCMs prepared for pharmaceutical cocrystals in future.

1. Introduction

Traditional Chinese Medicine (TCM) is the natural therapeutic agent used under the guidance of the theory of traditional Chinese medical science which has been widely used in China for thousands of years.¹⁾ Only less than 1% of the pharmaceutical ingredients derived from traditional Chinese medicines can been eventually commercialized since they suffer from poor physicochemical properties such as low aqueous solubility, poor stability, high hygroscopicity and erratic bioavailability.²⁾ There is plenty of treasure in traditional Chinese medicine to be dug up using contemporary scientific techniques. Cocrystallization is an effective and widely employed approach to modify the physicochemical properties of active pharmaceutical ingredients without changing their bioactivities since cocrystals are constructed using active pharmaceutical ingredients (APIs) and cocrystal formers (CCFs) through non-covalent bonds such as hydrogen bonds, van der Waals forces, aromatic π–π stacking.³⁾ So it is necessary to summary the cocrystals of APIs in TCMs, analysis the improvement in physicochemical properties of APIs in TCMs by cocrystallization and provide a meaningful reference for more and more APIs in TCMs prepared for pharmaceutical cocrystals in future. The 113 articles on cocrystals of traditional Chinese medicine have been selected in Web of Science and CNKI databases from 2010 to 2020. More than 30 APIs are classified into flavonoids, alkaloids, polyphenols, terpenoids, anthraquinones, and isocoumarins, which are summarized in Table 1.

Table 1. Classification of APIs in TCMs

API	CCF
Flavonoids
Luteolin	Isoniazid21) Caffeine21) DL-Proline22) 4,4′-Bipyridine23) Isonicotinamide24)
Fisetin	Nicotinamide24) Isonicotinamide24)
Baicalein	DL-Proline22) Caffeine25,26) Isoniazid26) Isonicotinamide26) Theophylline26,27,28) 4,4′-Bipyridine29) Nicotinamide30) Betaine31)
Phloretin	Betaine31)
Kaempferol	DL-Proline22) 4,4′-Bipyridine32,33,34)
Genistein	DL-Proline22) Nicotinamide24) 4,4′-Bipyridine35) Caffeine36) Isonicotinamide37)
Chrysin	DL-Proline22) Berberine38)
Myricetin	4,4′-Bipyridine34) Nicotinamide39) 4-Cyanopyridine39) Caffeine39,40,41) Isonicotinamide40) Proline42)
Dihydromyricetin	Urea43) Caffeine 43)
Daidzein	4,4′-Bipyridine44) Theophylline45)
Apigenin	Theophylline45) 4,4′-Bipyridine46)
Naringenin	Nicotinamide47,48) 2-Picolinic acid49) Betaine49) Isonicotinamide49,50,51)
Isoliquiritigenin	Nicotinamide52) Isonicotinamide52)
Quercetin	DL-Proline22) Betaine31) 4,4′-Bipyridine34) Isoniazid53) Theobromine54) Caffeine54,55) Nicotinamide54,55) Isonicotinamide56) 3,4-Dihydroxybenzoic acid57) 5-Sulfosalicylic acid57) Allopurinol57) 3-Hydroxybenzoic acid57) 3,4,5-Trihydroxybenzamide57) O-Acetylsalicylamide57) Pyrazole carboxamidine·HCl57) N-Acetylcytosine57) 2-Imidazolidinone57) Lactamide57) Urea57) L-Proline57) Baclofen57) Diflunisal57) L-Carnitine57) Dacarbazine57) Dipyridamole57) Piracetam57) Salicylamide57) Edaravone57) Kojic acid57)
Hesperetin	Caffeine58) Nicotinamide58) 2-Picolinic acid58)
Alkaloids
Caffeine	Malonic acid59) Maleic acid59) Glutaric acid59) Oxalic acid59,60) Urea61) Methyl gallate62) Citric acid63) Hemimellitic acid64) Trimesic acid64)
Theophylline	Trimesic acid64) Hemimellitic acid64) (Phenylthio)acetic acid65) Aspirin66) Acetaminophen67) Phthalic acid68) 4-Aminobenzoic acid69,70)
Theophylline	Anthranilic acid70) 3-Aminobenzoic acid70) 3-Hydroxybenzoic acid71) 4-Hydroxybenzoic acid71) 2,3-Dihydroxybenzoic acid71) 2,4-Dihydroxybenzoic acid71) 2,6-Dihydroxybenzoic acid71,72) 3,4-Dihydroxybenzoic acid71,72) 3,5-Dihydroxybenzoic acid71,72) 2,5-Dihydroxybenzoic acid71,73) Salicylic acid71,73,74) Orcinol72) Cinnamic acid72) Resorcinol72) 1,3,5-Trihydroxy benzene72) Maleic acid73) Sorbic acid73) 1-Hydroxy-2-naphthoic acid73) Nicotinamide73,75) Urea73,75) Oxalic acid73,76) Glutaric acid73,77) Saccharin75,78) Isonicotinamide77) Benzamide77,79,80) Acesulfame78) Acetamide80) Pyrazinamide80) Formamide80) N-Methylformamide80) N,N-Dimethylformamide80) Methyl gallate81) 4-Fluoro-3-nitrobenzoic acid82) Benzoic acid83) Pyridoxine84) Citric acid85)
Tetrahydropalmatine	Fumaric acid86) Methanesulfonic acid86) Sulfamic acid86) Maleicacid86) Camphorsulfonic acid86) 5-Sulfosalicylic acid86) p-Aminobenzenesulfonic acid86)
Berberine chloride	L (+)-lactic acid87) Fumaric acid88) Citric acid89) Succinic acid90) Glutaric acid90) Adipic acid90) Pimelic acid90) Pyromellitic dianhydride91) Dihydromyricetin92) Myricetin92) 4-Aminobenzoic acid93) 4-Hydroxybenzoic acid93) 2,6-Dihydroxybenzoic acid93) Rosiglitazone94)
Tetrahydroberberine	Phosphomolybdic acid95) Phosphotungstic acid95) Fumaric acid96) Oxalic acid96) Malonic acid96) Maleic acid96)
Polyphenols
Pterostilbene	Theophylline97,98) Ethylenediamine98) 1,4-Dimethylpiperazine98) 1,4-Diazabicyclo [2.2.2] octane98) Picolinic acid98) 1,4,8,11-Tetraazacyclotetradecane98) 2,3,5-Trimethylpyrazine98) Glutaric acid99) Piperazine99)
Resveratrol	Amantadine hydrochloride100) 4-Aminobenzamide101) Isoniazid101,102) Nicotinamide102) N,N-Dimethyl-4-aminopyridine103) Piperazine103) 4,4′-Bipyridine103) Phenazine103) 1,10-Phenanthroline103) Acridine103) Methenamine103) Succinimide103) 1,4-Diazabicyclo [2.2.2] octane103)
Oxyresveratrol	Nicotinamide104) Proline104) Citric acid105)
Ferulic Acid	Urea106) Isonicotinamide106) Nicotinamide106,107)
Curcumin	Resveratrol108) Trimesic acid109) L-Proline110) Catechol111,112) Hydroxyquinol112,113) Pyrogallol112,114) Resorcinol112,114) Hydroquinone112,115) Salicylic acid113) P-Hydroxybenzoic acid115) Ferulic acid115) L-Tartaric acid115) Nicotinamide115, 116) Lysine117) Ascorbic acid118) Phloroglucinol119)
Gallic acid	4-Cyanopyridine120) Succinimide121) Glutaric acid121) p-Aminobenzoic acid122) Aminoacetic acid122) 2,6-bis((pyridine-4-yl) methylene) cyclohexanone123) N-Methyl-3,5-bis((pyridine-3-yl) methylene)-4-piperidone123) N-Methyl-3,5-bis((pyridine-4-yl) methylene)-4-piperidone123)
Isocoumarins
Bergenin	4-Aminobenzamide124)
Anthraquinone
Emodin	Nicotinamide125,126) Benzamide126) 4,4′-Bipyridine126) Pyrimethamine126) Picolinamide126) Berberine chloride127)
Terpenes
Betulin	Adipic acid128) Terephthalic acid129)
Oleanolic acid	Succinic acid130) Saccharin130) L-Proline130)
Artesunate	4,4′-Bipyridine131)
Artemisinin	Orcinol132) Resorcinol132) Acetylenedicarboxylic acid133)

Flavonoids are polyphenols widely found in nature. Fifteen kinds of APIs such as luteolin, fisetin, baicalein, kaempferol, genistein, chrysin, daidzein, myricetin, dihydromyricetin, apigenin, naringenin, isoliquiritigenin, quercetin, phloretin and hesperetin belong to the flavonoids. Flavonoids have many medicinal values. For example, myricetin not only has antioxidant, anti-inflammatory, hepatoprotective, and antimicrobial,^4–6) but also affects the treatment of diabetes and cancer prevention.^7,8) Quercetin is famous for its antioxidant activity, and it is anticancer, bactericidal and antiviral.^9–11) Baicalein has been proved to have a variety of pharmacological activities, such as anticancer, anti-inflammatory, antibacterial, anti-human immunodeficiency virus and anti-lipogenesis. Several studies have shown that baicalein is also a potential therapeutic agent for the treatment of destructive diseases, such as Alzheimer and Parkinson.¹²⁾

Five APIs of alkaloids are caffeine, theophylline, tetrahydropalmatine, berberine chloride, and tetrahydroberberine. Theophylline is widely used as a bronchodilator in the treatment of asthma. Berberine chloride not only shows antibacterial activity, but also is a potential drug for the treatment of diabetes, hyperlipidemia, and cancer.

The six APIs such as pterostilbene, resveratrol, oxyresveratrol, ferulic acid, curcumin and gallic acid belong to polyphenols. Among them, resveratrol has been widely concerned for its extensive antibacterial, antioxidant, anti-inflammatory, and anti-cancer effects. Ferulic acid is a powerful phenolic antioxidant, which can absorb UV rays and is commonly used in skin care formulations as a photoprotective agent and delaying skin photoaging processes.¹³⁾ Moreover, ferulic acid is anti-inflammatory, anti-diabetic and anti-tumor.¹⁴⁾ Curcumin has various pharmacological activities, such as anti-inflammatory, anti-oxidation, and anti-cancer.¹⁵⁾

The four APIs such as betulin, oleanolic acid, artemisinin, and artesunate, belong to terpenoids. Artemisinin is the most promising antimalarial drug, which is effective and well tolerated by patients. Betulin is antibacterial, antiviral, anti-inflammatory, anti-AIDS, and anti-cancer.¹⁶⁾

There is only one API which is emodin belongs to anthraquinones. In addition to its various pharmacological activities such as vasorelaxant effects, antibacterial, anticancer and antidiabetic,^17–20) emodin is also an essential natural dye. The only API, bergenin, belongs to isocoumarins. Bergenin has the pharmacological effects of anti-oxidation, anti-microbial, anti-arthritis, anti-tumor, anti-inflammatory, liver protection, and neuroprotection.

2. ∆pK_a Rule

The contrast in pK_a value (∆pK_a) between acid and base is one of the most essential means to predict whether they produced cocrystals or salts. Generally speaking, when ∆pK_a < 0, the acid and base will form a cocrystal. when ∆pK_a > 3, they will create a salt, due to complete proton transfer. However, when 0 < ∆pK_a < 3, it is possible to create either a cocrystal or a salt.¹³⁴⁾

Supplementary Table S1 carries out the ∆pK_a calculation between each API and CCF in 113 literature reports on pharmaceutical cocrystals of APIs in TCMs. The pK_a values of APIs and CCFs were sourced from SciFinder, PubChem and DurgBank databases. A total of 220 cocrystals are included in the calculation except for several pK_a values of conjugate bases of APIs cannot be found. The formation of all of cocrystals is in accordance with ∆pK_a rule. When ∆pK_a value between each API and CCF is negative or higher than 0 and lower than 3, a cocrystal is formed. So the formation of cocrystal can be predicted by the ∆pK_a rule before the experiment.

3. Preparation Methods

There are many methods for the preparation of cocrystals, and the appropriate preparation method is usually selected according to whether the single crystal structure can be obtained, the screening of crystals, and the number of crystals required. The cocrystal preparation techniques in the set of APIs in TCMs are summarized in Table 2 and Fig. 1.

Table 2. Uses of the Preparation Methods for Cocrystals

Method	Single crystal	Screening	Scaling up
Evaporation cocrystallization	++	++	−
Grinding method	−	++	−
Suspension method	−	++	++
Cooling crystallization	−	+	++
Anti-solvent method	−	+	++

−: Fair, +: Good, ++: Very good.

Fig. 1. Statistical Chart on the Preparation Methods of Cocrystals in 113 Literature Reports

Evaporation cocrystallization is the most common method to prepare cocrystals since the pure and high-quality single crystals used for single crystal X-ray diffraction (SXRD) analysis can be produced by it and 44% of the cocrystals are prepared by it (in Fig. 1). However, this approach presents limitations, because it requires the solubilities of API and CCF are similar in the selected solvent to avoid single component precipitation. In addition to selecting a great variety of solvent systems, the cocrystal formation is affected by concentration, temperature, evaporation rate and so on, so screening is time and material consuming. Preparation of cocrystals by evaporation cocrystallization is a small-scale technique, which does not need complicated equipment. However, the use of large amounts of solvents and its limited expansibility are two downsides of this technique.

The grinding method is often used for the screening of cocrystals because only a minor amount of solvent or no solvent is added in the grinding process, which is cost-effective, simple to prepare, as well as environmentally friendly and does not need to consider the solubility differences of the API and CCF. Especially the liquid assisted grinding method with catalytic amount of solvent significantly enhanced efficiency, yield and crystallinity of the product along with an increased capacity to control polymorph creation. The liquid assisted grinding method often is used for screening potential cocrystals at small scales. As shown in Fig. 1, 27% of the cocrystals are prepared by the grinding method.

The suspension method is an effective method to screen cocrystals and 16% of the cocrystals are prepared by it (in Fig. 1). In this method, API and CCF are suspended in solvents according to a specific stoichiometric ratio, and stirred for a certain time. Then they are filtered and dried. Bučar et al. utilized the suspension method to screen cocrystals of theophylline with 9 different hydroxybenzoic acids.⁷¹⁾ Eight cocrystals and one salt were found. The suspension method is also commonly used for the mass preparation of cocrystals. For example, Sowa et al. provided a scale-up procedure for the preparation of the genistein-caffeine cocrystal by the suspension method, making it possible to determine its solubility.³⁶⁾

Cooling cocrystallization, antisolvent cocrystallization and other methods are also used to produce pharmaceutical cocrystals. In these 113 articles, when screening for cocrystals, the grinding method is the main method. The methods for the scale-up of cocrystal manufacturing mainly include the suspension method, the rotary evaporation method, the cooling cocrystallization method and the solvent precipitation method, and the suspension method is the first choice for laboratory scale-up preparation.

4. Characterization Techniques

A summary of the characterization techniques used for the reported APIs in TCMs is shown in Fig. 2. Powder X-ray diffraction (PXRD) is recognized as the “fingerprint” of crystals, and we can identify cocrystals or amorphous and crystallinity of the solid phase by the shape and intensity of diffraction peaks. The diffraction peaks of the cocrystal are compared with these of API and CCF to see if some diffraction peaks disappeared and new diffraction peaks appeared to judge whether the new phase is formed. Furthermore, PXRD technology is convenient, efficient, and has low requirements for the quality of cocrystals. Therefore, almost all cocrystals are characterized by PXRD.

Fig. 2. Statistical Chart on the Characterization Techniques Reported in 113 Literature Reports

SXRD is considered as the “gene” of crystals. SXRD provides the structure information of cocrystals, including the position of the atoms, molecules, and ions that make up the crystal in the unit cell, arrangement, bond length, bond angle, and so on. However, SXRD requires high-quality crystals, and we cannot always prepare perfect single crystals amenable to SXRD. There are 44% of cocrystals characterized by SXRD.

Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) are routinely used thermal analysis techniques for characterizing pharmaceutical cocrystals. Based on the weight loss of the TGA profile, we can judge whether there are solvent molecules in the cocrystal, and determine the change of crystal’s physical properties. The melting point of the cocrystal is often different from API and CCF. Therefore, we can identify the formation of cocrystals by the DSC thermogram. The joint technique of TGA-DSC is helpful in screening cocrystals. There are 81% of cocrystals characterized by thermal analysis techniques.

Many samples are analyzed by IR spectroscopy since IR operates faster and simpler. If there are new hydrogen bonds formed between API and CCF, the position of the absorption peaks of them in IR will undergo a corresponding shift. There are 60% of cocrystals characterized by IR.

Using NMR, we can confirm the stoichiometric ratio and the purity of cocrystals, and reveal the formation of cocrystals or salts. The single crystal of baicalein-D/L-proline suitable for diffraction cannot be obtained by various methods. The stoichiometric ratio of baicalein-D/L-proline is confirmed to be 1 : 1 by ¹H-NMR analysis.²²⁾ HEO·PyrH⁺Cl⁻ salt cocrystal possesses three OH and two NH hydrogen atoms (five HB donors) which positions are poorly established by SXRD. The formation of drug–drug salt cocrystal was confirmed by solid state NMR.⁸⁴⁾ There are 23% of cocrystals characterized by NMR.

Different CCF used for the cocrystallization of the same API may influence the particle size and morphology of cocrystals. Even the final particle morphology will also be different for the same cocrystal prepared by other cocrystallization methods. The size and morphology of the cocrystals have significant influence on the compactness, compressibility, and flowability.⁷³⁾ The particle size distribution and morphology of cocrystals are visualized clearly by scanning electron microscope (SEM). The cocrystals characterized by SEM accounted for 22%.

Other methods such as Raman spectroscopy and hot-stage microscopy (HSM) are also important characterization techniques for cocrystals. But they are relatively rarely used. There are 15 and 4% of cocrystals characterized by Raman and HSM, respectively.

5. Properties Study

In the 90 papers out of 113, it is reported that the research on physicochemical properties such as solubility, dissolution, bioavailability, stability, tabletability, and so on. The summary is shown in Fig. 3.

Fig. 3. Statistical Chart on the Research of Physicochemical Properties of Cocrystals in 90 Literature Reports

5.1. Solubility

There are forty papers in which it is described solubility in the context of cocrystallization. However, in six of them there was not quantified solubility change, although the enhanced solubilities of cocrystals were shown in five articles and the decreased solubility was shown in one paper.

The ratios of solubilities of cocrystals to these of APIs are shown in Fig. 4 from the remaining thirty-four literature reports. We found that the solubilities of most APIs in TCMs had been enhanced, and the increased ratios were mainly concentrated 1–10 times after the formation of cocrystals. Especially, the solubilities of cocrystals were improved over 100 times more than APIs in three literature reports.

Fig. 4. Scatter Plot of Improved Multiples of Solubility in 34 Literature Reports

Pantwalawalkar et al. prepared the curcumin-ascorbic acid cocrystal and measured its saturation solubility in distilled water, buffer (pH 1.2), and buffer (pH 6.8) at 37 °C, respectively. The results indicated that the solubility of curcumin-ascorbic acid cocrystal was significantly higher than that of curcumin. Especially in water, the solubility of curcumin was found to be significantly enhanced by 576 times.¹¹⁸⁾ Increased solubility of curcumin in the cocrystal system could be attributed to stronger molecular level interactions between curcumin and ascorbic acid favored by solvent (methanol).

Wang et al. synthesized the resveratrol-amantadine hydrochloride cocrystal. The solubility of resveratrol in hydrochloric acid solution with pH 1.2 was 0.031 mg/mL. In contrast, the solubility of resveratrol-amantadine hydrochloride cocrystal was 4.712 mg/mL, which was 152 times higher than that of pure resveratrol.¹⁰⁰⁾ The huge difference of thousands of times in solubility offers opportunities for resveratrol to have an increase in solubility by virtue of the advantage of amantadine hydrochloride. Furthermore, due to the hydrophilic and/or hydrophobic effects, as well as the alterations in polarity and crystal lattice due to the noncovalent interactions of amantadine hydrochloride with resveratrol, the bidirectional optimizations increase the solubility of the present cocrystal.

Li et al. prepared the cocrystal of berberine chloride with myricetin and found that the solubility of berberine chloride-myricetin cocrystal was 139.75 times higher than that of myricetin.⁹²⁾ The improvement of myricetin’s solubility correlated to the arrangement of crystal packing due to cocrystallization.

There are also several literature reports in which the aqueous solubilities of APIs were not enhanced, but were reduced. For example, Goldyn et al. prepared theophylline-trimesic acid, theophylline-trimesic acid·H₂O, caffeine-trimesic acid, caffeine-hemimellitic acid·H₂O cocrystals, and the solubilities in water were increased by 0.25, 0.24, 0.09 and 0.3 times respectively.⁶⁴⁾ In the paper, we found the solubility of trimesic acid (26.3 g/L) and hemimellitic acid (30.6 g/L) were not very higher than theophylline (8.3 g/L) and caffeine (16 g/L).

5.2. Dissolution and Dissolution Rate

There are fifty-three literature reports about dissolution and dissolution rate, and in eleven of them, the specific data about increased multiples of dissolution or dissolution rate were not reported. In these eleven papers, the dissolution properties of cocrystals were better than those of APIs in TCMs, except for the dissolution rate of theophylline-1-hydroxy-2-naphthoic acid, theophylline-saccharin, and theophylline-2,5-dihydroxybenzoic acid prepared by Padrela et al. was lower than that of theophylline.⁷³⁾

The ratios of the dissolution rates of cocrystals to these of APIs are shown in Fig. 5 from the remaining forty-two literature reports. The dissolutions of most APIs in TCMs have been improved, and the ratios are mainly concentrated in 1–10 after the formation of cocrystals. Bofill et al. prepared pterostilbene-picolinic acid cocrystal and the cocrystal showed 32.4-fold enhancement in the dissolution rate compared with pterostilbene.⁹⁸⁾

Fig. 5. Scatter Plot of Improved Multiples of Dissolution or Dissolution Rate in 42 Literature Reports

There are three papers in which it was reported that the dissolutions of cocrystals are reduced. For example, Guan et al. prepared the cocrystal of rosiglitazone with berberine chloride and measured the powder dissolutions of rosiglitazone, berberine chloride, and cocrystal in phosphate buffer (pH 6.8) containing 0.2% (w/v) of tween-80. The results showed that the dissolution of berberine chloride was 73% of the original, while that of cocrystal was only 51%.⁹⁴⁾

5.3. Bioavailability

There are twenty-one literature reports on bioavailability research. In only one article, the specific data on the improvement of bioavailability cannot be found, but the bioavailabilities of cocrystals in this paper is significantly higher than that of API.

The bioavailability ratios of cocrystals to APIs are shown in Fig. 6 from the remaining twenty literature reports. It is obvious that the bioavailabilities of APIs in TCMs have been improved by the formation of cocrystals, and the bioavailability ratios of cocrystals to APIs are largely concentrated in 1–5. The quercetin-isoniazid cocrystal prepared by Liu et al. registered the best bioavailability ratio, which is 28.91.⁵³⁾

Fig. 6. Scatter Plot of Improved Multiples of Bioavailability in 20 Literature Reports

5.4. Stability

There are twenty-nine literature reports on stability research. In these twenty-nine documents, the cocrystals exhibited more stability than APIs in wide ranges of humidity and temperature variations except for the cocrystals of quercetin, kaempferol, chrysin, genistein, baicalein with proline manufactured by He et al., the six cocrystals of tetrahydropalmatine with maleic acid, fumaric acid, methanesulfonic acid, sulfamic acid, camphorsulfonic acid, p-aminobenzenesulfonic acid prepared by Su, and caffeine-glutaric acid (Form I) cocrystal prepared by Trask.^22,86,59)

Berberine chloride (BCl) can exist in the forms such as anhydrate, monohydrate, dihydrate and tetrahydrate. The solid phase transition of BCl will encounter with the change of environmental humidity during the manufacturing and storage of tablets.⁸⁹⁾ Wang et al. prepared the cocrystal of BCl with succinic acid (BCl-SUA), which absorbed only 0.9% of water when RH reached 95%. The hygroscopicity of cocrystal was substantially lower than BCl.⁹⁰⁾

5.5. Tabletability

There are only seven literature reports on the research for tabletability. In these seven literature reports, curcumin possesses poor compressibility, but the cocrystals of curcumin with six conformers such as catechol, resorcinol, hydroquinone, pyrogallol, hydroxyquinol, and phloroglucinol are superior to curcumin in compressibility.^112,119)

However, the cocrystals of caffeine-oxalic acid, theophylline-methyl gallate and theophylline-4-fluoro-3-nitrobenzoic acid displayed poor tabletability behavior compared with API.^60,81,82) The tableting capacity of the cocrystal of BCl and citric acid was significantly better than citric acid, and there was no practical difference in tableting between the cocrystal and BCl dehydrate, which is the form used in production.⁸⁹⁾

6. Conclusion

In the reported cocrystals of APIs in TCMs, there are most cocrystals in flavonoids, followed by alkaloids and polyphenols.

Generally, we select CCFs, and predict the formation of salts according to the ∆pK_a rule. By summarizing the cocrystals of APIs in TCMs, we found that in all cases, the formation of cocrystals is in accord with the ∆pK_a rule.

Since evaporation cocrystallization can grow single crystals amenable to SXRD determination, it is the most commonly used method for preparing cocrystals. The grinding method conforms to the concept of green chemistry due to the absence of any solvent or only a tiny amount of solvent, and it is often used to screen cocrystals. The number of this method used in 113 literature reports is second to the solvent evaporation method. The study of some properties of cocrystals requires to use a large number of samples, and the suspension method is a kind of cocrystal preparation method suitable for amplification, so suspension method is also a common method to prepare cocrystals.

Since cocrystals exhibit characteristic peaks compared to starting materials, PXRD is used in almost all papers for screening and verification. Thermal analysis techniques such as TGA, DSC, and HSM are also commonly used to screen whether cocrystals are formed or not. SXRD is adequate for crystal structural determination, but single crystals which are suitable for SXRD are not always available. NMR can also provide the number of independent molecules in a unit cell, whether it is disordered, the properties of hydrogen bonds, the characteristics of salts or cocrystals, and the presence of water and solvent molecules. NMR can also determine the stoichiometric ratio of cocrystals. Therefore, NMR can be used as a supplement to SXRD. IR and Raman spectra are non-destructive analysis techniques, which are simple and efficient, and using a small number of samples. They are also commonly used in the characterization of cocrystals.

The preparation of cocrystals is mainly used to improve the solubility of poorly soluble drugs and thus improve bioavailability. Therefore, in the research of cocrystal properties, solubility and dissolution are studied most, followed by bioavailability and hygroscopicity, and in only a few literature reports, the tabletability has been studied. Pharmaceutical cocrystals are mainly formed by some non-covalent bonds, which are connected and combined in the same lattice form. In the non-covalent bonds, the strength of the hydrogen bond is relatively large. Therefore, the solubility, dissolution, and bioavailability of low-solubility API can be improved by forming cocrystals. The improved multiples are primarily concentrated in 1–10. In some cases, the solubilities and dissolutions of some insoluble APIs have been increased by dozens or hundreds of times through cocrystallization technology. So cocrystallization is very effective on the 1–10 fold improvement in solubility and absorption of APIs in TCMs. There are plenty of APIs in TCMs with poor physicochemical properties to be dug up using cocrystallization technique.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

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