Int J Pharm Pharm Sci, Vol 16, Issue 6, 27-32Review Article

ADVANCES IN COCRYSTALS OF ANTICANCER AGENTS: FORMULATION STRATEGIES AND THERAPEUTIC IMPLICATIONS

APARNA SINGH, VISHAKHA JAISWAL*, SHRADHA BISHT

Amity Institute of Pharmacy, Lucknow, Amity University Uttar Pradesh, Sector 125, Noida-201313, India
*Corresponding author: Vishakha Jaiswal; *Email: vishakhajaiswal216@gmail.com

Received: 24 Mar 2024, Revised and Accepted: 22 Apr 2024

ABSTRAC

Cancer remains one of the most pressing health concerns worldwide, driving continuous efforts in pharmaceutical research to develop more effective treatments. In the ever-evolving landscape of cancer therapy, cocrystals stand as promising contenders, offering enhanced solubility, stability, and bioavailability to traditional anticancer agents. Co-crystallization, a strategy emerging at the nexus of pharmaceutical and crystal engineering. From the fundamental principles of cocrystal engineering to advanced spectroscopic and crystallographic methodologies, each aspect is meticulously dissected to unveil the transformative potential of cocrystals in oncology. The review elucidates the transformative potential of cocrystals in oncology, highlighting their capacity to revolutionize drug delivery and efficacy. Recent advancements in the field are comprehensively examined, showcasing the promising role of anticancer cocrystals in paving the way for novel therapeutic strategies and improved patient outcomes. Cocrystals represent a promising avenue in cancer therapy, offering significant enhancements to traditional anticancer agents. Through a comprehensive exploration of recent advancements, this article navigates the complex terrain of anticancer cocrystals, drug-drug cocrystals, paving the way for novel therapeutic strategies and improved patient outcomes.

Keywords: Cocrystal, Cancer, Drug-drug co-crystal, Co-former, Green synthesis, Synthon approach

© 2024 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/)
DOI: https://dx.doi.org/10.22159/ijpps.2024v16i6.51044 Journal homepage: https://innovareacademics.in/journals/index.php/ijpps

INTRODUCTION

Cancer stands as a prominent catalyst for the escalating global mortality rates and remains a paramount public health challenge worldwide [1]. With one in every six deaths attributed to cancer, its impact on mortality rates cannot be overstated [2]. The Global Cancer Observatory (GCO) projects a staggering 10 million deaths related to cancer, alongside an estimated 19 million new cases in the year 2020 alone [3]. Despite these stark statistics underscoring the ongoing battle against cancer, it is disheartening to note that the "war on cancer" remains far from won, as evidenced by projections indicating a staggering toll of sixteen million lives lost and three billion new cases globally over the next decade [4].

The spectrum of cancers is vast and encompasses a myriad of types, including but not limited to kidney cancer, pancreatic cancer, uterine cancer, bladder cancer, skin cancer, prostate cancer, non-Hodgkin lymphoma, leukemia, endometrial cancer, colorectal cancer, lung cancer, melanoma, breast cancer, liver cancer, and thyroid cancer [5]. Refer to fig. 1 for an illustration depicting data and facts concerning various cancer types.

Fig. 1: Statistical data and factual information regarding various types of cancer [6]

Over the past decade, healthcare professionals have grappled with heightened cancer prevalence. Progress in science and technology has been instrumental in addressing gaps in the field, particularly in advancing medicinal treatments. Historically, cancer treatment primarily relied on parenteral administration, but in recent decades, oral administration has gained traction due to its convenience and dosing frequency [7].

Oral drug delivery stands out as a popular and well-established method, offering benefits such as enhanced patient comfort, acceptability, and safety. The customisable nature of formulations based on the physicochemical properties of medicinal ingredients adds to their appeal within the scientific community. However, the efficacy of orally administered cancer chemotherapeutic drugs is impeded by challenges like the significant first-pass effect, higher efflux ratio, lower water solubility, impermeability, and reduced bioavailability [8].

Anticancer drugs constitute about 75% of newly developed chemical compounds, which are predominantly known for their poor water solubility [9]. This limited solubility poses a significant challenge to their development and practical application. According to the Biopharmaceutics Classification System (BCS), drugs are categorized as weakly water-soluble if their highest dosage strength fails to dissolve in 250 ml or less of water across a pH range of 1 to 7.4 [10]. Unfortunately, numerous anticancer drugs such as dasatinib [11], curcumin [12], docetaxel [13], and paclitaxel [14] fall into BCS classes II and IV due to their low solubility. Despite this challenge, many of these drugs possess potential antineoplastic efficacy. Their high lattice energies render them less soluble than micrograms per millilitre, hindering their dissolution and interaction with water molecules [15].

Since oral administration remains the most feasible route, over 80% of commercial drugs are formulated in solid doses like tablets and capsules [16]. In solid-state formulations, the physicochemical properties of drugs can be modified using methods such as co-crystals, polymorphs, salts, amorphous forms, and hydrates [17]. However, due to the risk of polymorphic transformation, which can impact the final product, polymorphs are generally not recommended [18]. Consequently, new strategies must be devised to modify or improve the physicochemical properties of these drugs [19].

Co-crystals, as defined by the Food and Drug Administration (FDA), are crystalline solids comprising two or more distinct molecules. In pharmaceutical contexts, Active Pharmaceutical Ingredients (APIs) often engage in crystal lattice formation through non-ionic interactions with co-formers or co-crystal formers (Food and Drug Administration, 2018). Over recent years, co-crystals have shown significant advancement in drug development, particularly in modifying the physicochemical and pharmacokinetic attributes of APIs. These modifications include enhancements in solubility, dissolution rate, particle size, melting point, bioavailability, morphology, biochemical stability, physical form, and permeability [20]. Additionally, numerous research studies have explored the application of co-crystals in drug delivery [21].

Moreover, Yuliandra et al.'s investigation into the in vivo efficacy of the ibuprofen-nicotinamide (IBU-NIC) co-crystal in male Swiss-Webster rats demonstrated that co-crystal production could enhance the analgesic effectiveness of the compound. Results indicated a doubling in pain inhibition with the IBU-NIC co-crystal compared to ibuprofen alone or its physical combination [22, 23]. Moreover, as depicted in fig. 2, active pharmaceutical ingredients (APIs) can create multi-component crystals in a singular form.

Fig. 2: Various pharmacological forms for API that are solid and multicomponent [24]

Lawton and Lopez did not introduce the term "co-crystal" until 1963. Co-crystals are characterized as multicomponent crystals consisting of co-formers and APIs, featuring non-covalent intermolecular bonding interactions such as van der Waals forces, π-π stacking, hydrogen bonds, and halogen bonds. Supramolecular synthons, alternatively known as homo-or hetero-synthons, emerge when functional groups within a crystal repeatedly interact with one another through proton donors and acceptors. These synthons may comprise identical functional groups or diverse ones [19].

The data was collected from Elsevier-Science Springer Link, PubMed, National Library of Medicine (NLM), Semantic Scholar, and Google Scholar to conduct a literature search mostly from 2022 to 2024. The reference articles selected for this work are those that describe the current trends in co-crystallization techniques, characterization spectral techniques used, latest drug cocrystals for various cancer for management purpose, patient care and improving quality of life.

Co-former screening and selection techniques

Selecting the perfect co-former is imperative for accessing cocrystals with desired qualities. Simultaneously, the crystal engineering of APIs poses a formidable task. The process of cocrystal formation faces its greatest challenge during the selection of suitable co-formers, as the array of potential candidates often exceeds hundreds and multiple validation methods are commonly employed [25]. Supramolecular chemistry underpins the synthesis of cocrystals, with hydrogen bonding being the predominant intermolecular bonding motif among most APIs and co-formers. Thus, the choice of the optimal co-former remains pivotal for achieving cocrystals with the desired attributes [26].

Theoretical approaches

Various theories, including "Hydrogen bonding propensity," "Cambridge Structure Database," "supramolecular synthon," "acid dissociation constant (pKa) values," and "Hansen solubility parameters," were utilized in elucidating the genesis of cocrystals [27]. Etter's pragmatic directives on hydrogen bonding for constructing such solids could provide the fundamental framework for understanding hydrogen bonding synthons in cocrystals. Etter's investigation into the controllability of hydrogen bonding within established crystal structures aimed to regulate the hydrogen-bond assembly of chemical compounds generating crystals. Consequently, he proposed a series of pragmatic principles governing hydrogen bonding [27, 28]. The subsequent elucidation outlines Etter's trio of hydrogen-bonding guidelines:

a) All reliable proton donors and acceptors participate in hydrogen bonding.

b) Six-membered-ring intramolecular hydrogen bonds form, unlike intermolecular hydrogen bonds.

c) Following the establishment of intramolecular hydrogen bonds, the remaining proton donors and acceptors above create intermolecular hydrogen bonds with each other.

Supra molecular synthon approach

Cocrystals emerge from noncovalent interactions between a drug and co-formers, such as hydrogen bonds, van der Waals forces, and pi-pi stacking. Supramolecular synthons, defined as structural units within super molecules, can be formed through known or anticipated synthetic methods involving intermolecular interactions, as proposed by Desiraju's [29] model of the supramolecular synthon approach. The process of designing cocrystals using the H-bonding rule of the supramolecular synthons approach is illustrated in fig. 3.

a) Identifying functional groups within the active pharmaceutical ingredient (API) and co-former molecules.

b) evaluating intramolecular interactions within the isolated molecules of the desired compounds.

c) recognizing potential functional groups that could hinder intramolecular interactions in pure compounds.

d) evaluating the probability of intermolecular interactions between different molecules.

e) choosing co-formers through analysing both intramolecular and intermolecular interactions.

Cambridge Structural Database (CSD)

The CSD serves as a crucial tool in elucidating intermolecular hydrogen bonding within crystals [30], playing a pivotal role in advancing various fields such as chemistry, materials science, life sciences, and pharmaceutical research. With its robust design and efficiency, the CSD continually incorporates approximately 40,000 new structures annually [31]. Furthermore, it can be leveraged to anticipate stable hydrogen bond motifs, thereby preserving the most robust patterns across a range of core structures. Additionally, the CSD offers the advantage of facilitating the development of cocrystals through techniques like the hydrogen bonding potential (HBP).

Fig. 3: Hydrogen bonding between suitable functional groups of drugs and co-former according to supramolecular synthon approach [29]

Preparation methods of co-crystals

The two most common methods of cocrystal production are solution crystallization and solid-state crystallization. The methods used to generate cocrystals can be broadly divided into three categories: solvent-based, supercritical fluid approaches, and green synthesis methods (also known as non-solvent-based methods) [32].

Green synthesis techniques or non-solvent techniques

Non-solvent techniques offer environmental advantages as they require minimal or no solvent for the creation of cocrystals. These methods, namely Liquid-Assisted grinding (LAG), extrusion, simple/neat grinding, and hot-melt extrusion, fall into four distinct categories [33]. The neat grinding approach involves blending two or more co-formers according to a predetermined stoichiometry and then mechanically or physically grinding them for a set duration. Except for the minimal use of organic solvent during grinding, the LAG method closely resembles neat grinding [34]. In the extrusion process, co-formers and the Active Pharmaceutical Ingredient (API) are combined below the raw material's melting point using either a single screw or twin screws. Conversely, hot-melt extrusion is a specialized technique that simultaneously melts and mixes co-formers using a hot screw extruder [35].

Solvent-based techniques

Various solution-based techniques, including evaporative, spray drying, solvent evaporation, slurry, and reactive co-crystallization, are recognized for their ability to produce cocrystals. Solvent serves as a medium in the co-crystallization process, involving undersaturated solutions of both the co-former and the API [36]. Formation of ketoprofen-malonic acid cocrystal by solvent evaporation method. This method typically yields single-crystal cocrystals suitable for diffraction studies and crystal structure characterization. Similarly, assisted evaporation co-crystallization, conducted under controlled conditions, resembles the solvent evaporation method but occurs at higher temperatures and/or lower pressure [37].

Although spray drying is commonly employed for producing amorphous solid dispersions (ASDs), recent research indicates its potential for cocrystal synthesis. This method offers advantages due to its rapid, continuous, and precise control over the process. In spray drying, a sprayer disperses an unsaturated liquid containing both drugs and co-formers with nitrogen, facilitating rapid solvent removal and solid particle formation [38].

The slurry conversion technique, often known as isothermal slurry conversion, involves introducing solid co-formers to a solvent (or a blend of solvents) at a predetermined stoichiometric ratio to achieve equilibration. Unlike evaporative co-crystallization, this method doesn't necessitate a clear starting solution.

In reactive co-crystallization, co-formers and APIs are separately mixed before being introduced to one of the clear solutions, leading to spontaneous co-crystallization. Nanocrystal formulations can be prepared using the ultrasound-assisted solution technique, where suitable co-formers and APIs are dissolved in a solvent. The solution undergoes sonication at a controlled temperature to prevent fragmentation and degradation, followed by overnight incubation for solvent evaporation and cocrystal formation [39].

Supercritical fluid approach

To produce a single crystal from a complex system of multiple components, the supercritical fluid method involves heating a mixture of Active Pharmaceutical Ingredient (API) and co-former to a temperature near the melting point of one component, typically the co-former. Unlike traditional organic solvents, supercritical fluid facilitates rapid kinetics and simplifies solvent removal from the final products, reducing costs and equipment requirements for subsequent steps in cocrystal production. This technique relies on suspending both API and co-former in a supercritical CO2 slurry for co-crystallization. By adjusting CO2 thermodynamics to maintain its density and solvent power, control over co-crystallization between components is achieved.

The use of this method has demonstrated accelerated co-crystallization rates, resulting in complete co-crystallization and the formation of pure cocrystals due to efficient mass transfer facilitated by convection in the CO2 slurry. In the Rapid Expansion of Supercritical Solvents (RESS) method, supercritical CO2 saturated with API and co-former is depressurized through a nozzle into an atmospheric drying chamber. However, many pharmaceutical compounds do not exhibit the required solubility in supercritical CO2 for this approach.

In the Supercritical Antisolvent Co-crystallization (SAC) procedure, supercritical CO2 serves as an antisolvent. This method precipitates both molecules together as a single unit and requires less soluble API and co-former compared to RESS. Upon the introduction of components into the vessel, CO2 dissolves in the solvent, expanding the volume while reducing solvent solubility and precipitating the solvent.

In the batch gas antisolvent (BGAS) method, a solution containing both API and co-former is saturated in a vessel with carbon dioxide under increased pressure until co-crystallization is achieved. Alternatively, the semi-continuous supercritical antisolvent (SSAS) technique utilizes a sprayer to inject an API-co-former solution into a vessel containing supercritical CO2 under high pressure [40].

Characterization of cocrystals

Microscopic, spectroscopic, and thermal techniques are commonly employed in the analysis of cocrystals. Various physicochemical factors such as crystallinity, melting temperature, stability, dissolution, and solubility are assessed similarly to any other solid form to ascertain the suitability of a substance for industrial dosage formulation. The melting point, a crucial physical characteristic determined by the temperature at which the solid and liquid phases reach equilibrium with zero free energy of transition, is fundamental. Differential scanning calorimetry (DSC) efficiently provides melting point and thermal data like melting enthalpy. Additionally, Differential Thermal Analysis (DTA) and Thermogravimetry (TG) are employed to ascertain factors such as polymorphisms, glass transitions, hydration, decomposition, and stability.

Powder X-ray diffraction and single-crystal X-ray diffraction offer structural information, crystallinity level, and crystal size. Single-crystal X-ray diffraction (SCXRD) is considered the gold standard for comprehensive 3D structural, compositional, packing, and hydrogen bond information. Spectrophotometric methods like Infrared Radiation (IR), Raman, and nuclear magnetic resonance (NMR) offer insights into noncovalent interactions, such as hydrogen bonds, and detect shifts in intermolecular interactions across various crystal structures. Scanning electron microscopy (SEM) and optical microscopy are utilized for surface topography examination, particle size analysis, and optical property assessment.

Hot-stage microscopy (HSM) integrates microscopy and thermal analysis to provide solid-state characterization, especially for temperature assessment. Stability in both solid and liquid states is crucial for orally administered dosage forms. Thermal and relative humidity stress (RHS) are used to assess the potential for solid-state modifications. High-performance liquid chromatography (HPLC) is often combined with thermal techniques and powder X-ray diffraction (PXRD) for degradation testing.

Distinguishing between salt and cocrystal can be challenging. Solid-state NMR and/or IR spectra can aid in estimating proton transfer, though interpretation in a specific system may be difficult. SCXRD remains the most reliable method for identifying salt or crystals, while others are indirect and prone to error [41].

Application of drug cocrystals in the realm of cancer treatment

Teva Pharmaceuticals has recently combined fumaric acid with the anticancer medication ibrutinib, commonly prescribed for chronic lymphocytic leukaemia, to create a cocrystal. This innovative blend, demonstrated to be more stable while maintaining comparable solubility to the original medication, presents ample opportunity for further cocrystal development. Researchers have successfully improved the physicochemical properties of numerous anticancer medications through the creation of various cocrystals. These cocrystals often incorporate carboxylic acids, polyphenols, carboxyl amides, and amides as co-formers due to their similar pKa values. Some anticancer medications, such as paclitaxel, exhibit zwitterionic properties. The majority of these medications are either mildly basic or weakly acidic [19].

The pKa rule of 3 suggests that cocrystal formation is facilitated when the pKa values of the drug and co-former fall within a range of 0 to 3. Using the ∆pKa rule, da Silva and colleagues synthesized cocrystals of 5-fluorocytosine with various co-formers, including terephthalic acid, benzoic acid, adipic acid, succinic acid, and malic acid [42].

In another study, Chenxin et al. investigated two distinct co-formers for palbociclib, utilizing orcinol and resorcinol. Palbociclib-resorcinol cocrystals exhibited enhanced powder dissolution compared to pure palbociclib. However, a notable drawback was observed: while these cocrystals improved the drug's solubility, they also increased its bioavailability [43].

Table 1: A list of anti-cancer medication cocrystals that have been described, along with cocrystal synthesis methods and enhanced properties from pure API

Anti-cancer drugs Co-formers Preparation techniques Enhanced parameters from pure drug Reference
5-Fluorouracil Ferulic acid Solvent assisted co-grinding Improved solubility and permeability [44]
5-Fluorouracil Proline Solvent evaporation technique and Liquid assisted grinding Improved solubility, permeability [45]
4,40–ethylene bis pyridine Flavonoids Solvent Evaporation method Improved dissolution behaviour and anti-tumor activity [46]
5-Fluorouracil Succinic acid, Malic acid Cinnamic acid, and Benzoic acid Neat grinding and slow solvent evaporation Improved anticancer activity [47]
6-Mercaptopurine monohydrate 2,4-Dihydroxybenzoic acid and Hydroxybenzoic acid Slurry reactive crystallization Improved solubility and stability [48]
Axitinib Glutaric acid Solvent evaporation technique Improved solubility and stability [49]

Drug-drug cocrystals (DDC)

Drug-drug cocrystals represent a novel class of solid forms comprising two or more active pharmaceutical ingredients (APIs). They present a promising solution to the challenges associated with traditional combination therapies. DDCs offer potential as a solid-state platform for dual drug delivery, altering the physicochemical properties of constituent medications. Compared to other combination approaches, DDC technology can enhance API characteristics such as bioavailability, stability, and lifecycle management while potentially improving dissolution rates [50].

In a study by Carmen [51], a cocrystal of celecoxib (CTC) and tramadol hydrochloride was examined. Dissolution trials revealed a slower release of tramadol hydrochloride and an increased intrinsic dissolution rate (IDR) of celecoxib in the cocrystal. Comparative pharmacokinetic analysis with open combinations and single-entity reference products showed a favourable change in clinical profile. Celecoxib was absorbed more rapidly from CTC than tramadol, resulting in a decreased peak plasma concentration (Cmax). Phase II clinical trials demonstrated superior analgesic efficacy of CTC over tramadol and celecoxib in treating moderate to severe pain post-dental extraction involving bone removal. Additionally, this DDC formulation offers additional intellectual property protection, potentially extending the patent life of both tramadol and celecoxib.

CONCLUSION

In recent years, cocrystals have garnered significant attention from scientists owing to their perceived low risk, affordability, and multifaceted advantages. Despite this, the body of research literature on cocrystal remains relatively sparse, and commercially available cocrystal are in short supply. Pharmaceutical researchers face challenges in predicting cocrystal development, understanding supramolecular interactions, and elucidating cocrystal association and dissociation patterns. Overcoming these challenges requires the development of novel crystallization technologies and more efficient screening protocols. Additionally, expanding cocrystals to include drug-nutraceutical combinations could unlock new possibilities for drug combinations and innovative medication applications. This exploration has explored various formulation strategies and therapeutic implications, highlighting the potential of cocrystals to enhance drug solubility, bioavailability, and stability, thus pushing the boundaries of conventional pharmaceutical formulations.

FUNDING

Nil

AUTHORS CONTRIBUTIONS

All authors have contributed equally

CONFLICT OF INTERESTS

Declared none

REFERENCES

  1. Novais MV, Gomes ER, Miranda MC, Silva JO, Gomes DA, Braga FC. Liposomes co-encapsulating doxorubicin and glucoevatromonoside derivative induce synergic cytotoxic response against breast cancer cell lines. Biomed Pharmacother. 2021 Apr 1;136:111123. doi: 10.1016/j.biopha.2020.111123, PMID 33486211.

  2. Layek B, Gidwani B, Tiwari S, Joshi V, Jain V, Vyas A. Recent advances in lipid-based nano drug delivery systems in cancer therapy. Curr Pharm Des. 2020 Aug 1;26(27):3218-33. doi: 10.2174/1381612826666200622133407, PMID 32568015.

  3. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-49. doi: 10.3322/caac.21660, PMID 33538338.

  4. Lambert JM, van Delft FL. Introduction to antibody-drug conjugates. In: van De FL and Lambert JM. editors. Chemical linkers in antibody-drug conjugates (ADCs). Royal Society of Chemistry; 2021. p. 1-31.

  5. Cooper GM, Hausman RE. The development and causes of cancer. Cell Mol Biol. 2000;2:719-28.

  6. Kara DD, Rathnanand M. Cocrystals and drug-drug cocrystals of anticancer drugs: A perception towards screening techniques, preparation, and enhancement of drug properties. Crystals. 2022 Sep 21;12(10):1337. doi: 10.3390/cryst12101337.

  7. Sawicki E, Schellens JH, Beijnen JH, Nuijen BJ. Inventory of oral anticancer agents: pharmaceutical formulation aspects with focus on the solid dispersion technique. Cancer Treat Rev. 2016 Nov 1;50:247-63. doi: 10.1016/j.ctrv.2016.09.012, PMID 27776286.

  8. Sohail MF, Rehman M, Sarwar HS, Naveed S, Salman O, Bukhari NI. Advancements in the oral delivery of docetaxel: challenges, current state-of-the-art and future trends. Int J Nanomedicine. 2018 Jun 8;13:3145-61. doi: 10.2147/IJN.S164518, PMID 29922053.

  9. Han W, Xie B, Li Y, Shi L, Wan J, Chen X. Orally deliverable nanotherapeutics for the synergistic treatment of colitis-associated colorectal cancer. Theranostics. 2019;9(24):7458-73. doi: 10.7150/thno.38081, PMID 31695780.

  10. Gala UH, Miller DA, Williams III RO. Harnessing the therapeutic potential of anticancer drugs through amorphous solid dispersions. Biochim Biophys Acta Rev Cancer. 2020 Jan 1;1873(1):188319. doi: 10.1016/j.bbcan.2019.188319, PMID 31678141.

  11. Chavda H, Patel C, Anand I. Biopharmaceutics classification system. Syst Rev Pharm. 2010;1(1):62. doi: 10.4103/0975-8453.59514.

  12. Suzuki M, Takebe G, Takagi T, Tsukada H. Characterization of novel paclitaxel nanoparticles prepared by laser irradiation. Chem Pharm Bull (Tokyo). 2022 Apr 1;70(4):269-76. doi: 10.1248/cpb.c21-00994, PMID 35370203.

  13. Parvataneni DM, Devraj R, Mangamoori LN. Micelles entrapped microparticles technology: a novel approach to resolve dissolution and bioavailability problems of poorly water-soluble drugs. J Microencapsul. 2020 Apr 2;37(3):254-69. doi: 10.1080/02652048.2020.1729883, PMID 32052664.

  14. Ashrafizadeh M, Ahmadi Z, Mohamadi N, Zarrabi A, Abasi S, Dehghannoudeh G. Chitosan-based advanced materials for docetaxel and paclitaxel delivery: recent advances and future directions in cancer theranostics. Int J Biol Macromol. 2020 Feb 15;145:282-300. doi: 10.1016/j.ijbiomac.2019.12.145, PMID 31870872.

  15. Guo W, Du S, Lin Y, Lu B, Yang C, Wang J. Structural and computational insights into the enhanced solubility of dipfluzine by complexation: salt and salt-cocrystal. New J Chem. 2018;42(18):15068-78. doi: 10.1039/C8NJ01576G.

  16. Tran PH, Lee BJ, Tran TT. Strategies and formulations of freeze-dried tablets for controlled drug delivery. Int J Pharm. 2021 Mar 15;597:120373. doi: 10.1016/j.ijpharm.2021.120373, PMID 33577912.

  17. Khanfar M, Al-Remawi M, Al-Akayleh F, Hmouze S. Preparation and evaluation of co-amorphous formulations of telmisartan-amino acids as a potential method for solubility and dissolution enhancement. AAPS PharmSciTech. 2021 Apr;22(3):112. doi: 10.1208/s12249-021-01952-9, PMID 33748914.

  18. Karki S, Friscic T, Fabian L, Laity PR, Day GM, Jones W. Improving mechanical properties of crystalline solids by cocrystal formation: new compressible forms of paracetamol. Adv Mater. 2009 Oct 19;21(38-39):3905-9. doi: 10.1002/adma.200900533.

  19. Aitipamula S, Tan BH. Pharmaceutical co-crystals: crystal engineering and applications. Multi-component crystals: synthesis, concepts, function Tiekink ER, Schpector JZ, editors; 2018. p. 1-27.

  20. Ferretti V, Dalpiaz A, Bertolasi V, Ferraro L, Beggiato S, Spizzo F. Indomethacin co-crystals and their parent mixtures: does the intestinal barrier recognize them differently? Mol Pharm. 2015 May 4;12(5):1501-11. doi: 10.1021/mp500826y, PMID 25794305.

  21. Nugrahani I, Parwati RD. Challenges and progress in nonsteroidal anti-inflammatory drugs co-crystal development. Molecules. 2021 Jul 9;26(14):4185. doi: 10.3390/molecules26144185, PMID 34299458.

  22. Yuliandra Y, Zaini E, Syofyan S, Pratiwi W, Putri LN, Pratiwi YS. Cocrystal of ibuprofen nicotinamide: solid-state characterization and in vivo analgesic activity evaluation. Sci Pharm. 2018;86(2):23. doi: 10.3390/scipharm86020023, PMID 29867030.

  23. Aitipamula S, Banerjee R, Bansal AK, Biradha K, Cheney ML, Choudhury AR. Polymorphs, salts, and cocrystals: what’s in a name? Cryst Growth Des. 2012 May 2;12(5):2147-52. doi: 10.1021/cg3002948.

  24. Cerreia Vioglio PC, Chierotti MR, Gobetto R. Pharmaceutical aspects of salt and cocrystal forms of APIs and characterization challenges. Adv Drug Deliv Rev. 2017 Aug 1;117:86-110. doi: 10.1016/j.addr.2017.07.001, PMID 28687273.

  25. Malamatari M, Ross SA, Douroumis D, Velaga SP. Experimental cocrystal screening and solution-based scale-up cocrystallization methods. Adv Drug Deliv Rev. 2017 Aug 1;117:162-77. doi: 10.1016/j.addr.2017.08.006, PMID 28811184.

  26. Kara DD, Rathnanand M. Cocrystals and drug-drug cocrystals of anticancer drugs: a perception towards screening techniques, preparation, and enhancement of drug properties. Crystals. 1337;12(10). doi: 10.3390/cryst12101337.

  27. Etter MC. Hydrogen bonds as design elements in organic chemistry. J Phys Chem. 1991 Jun;95(12):4601-10. doi: 10.1021/j100165a007.

  28. Sopyan IY, Alvin B, Insan Sunan KS, Megantara SA. Systematic review: co-crystal as efforts to improve physicochemical and bioavailability properties of oral solid dosage form. Int J App Pharm. 2021 Jan 7;13(1):43-52. doi: 10.22159/ijap.2021v13i1.39594.

  29. Yadav S, Gupta PC, Sharma N, Kumar J. Cocrystals: an alternative approach to modify physicochemical properties of drugs. J Pharm Chem Biol Sci. 2015 Apr 1;5(2).

  30. Devogelaer JJ, Brugman SJ, Meekes H, Tinnemans P, Vlieg E, de Gelder R. Cocrystal design by network-based link prediction. Cryst Eng Comm. 2019;21(44):6875-85. doi: 10.1039/C9CE01110B.

  31. Devogelaer JJ, Meekes H, Tinnemans P, Vlieg E, De Gelder R. Co‐crystal prediction by artificial neural networks. Angew Chem Int Ed Engl. 2020 Nov 23;59(48):21711-8. doi: 10.1002/anie.202009467, PMID 32797658.

  32. Buddhadev SS, Garala KC. Pharmaceutical cocrystals-a review. Proceedings. 2020;62(1):14. doi: 10.3390/proceedings2020062014.

  33. Saraf GJ, Burade KK, Gonjari ID, Hosmani AH, Pawar AA. A review on advances in pharmaceutical co-crystal preparation routes, intellectual property perspective and regulatory aspects. Int J Curr Pharm Sci. 2022 Sep 15;14(5):4-12. doi: 10.22159/ijcpr.2022v14i5.2038.

  34. Medina C, Daurio D, Nagapudi K, Alvarez Nunez F. Manufacture of pharmaceutical co‐crystals using twin screw extrusion: a solvent‐less and scalable process. J Pharm Sci. 2010 Apr 1;99(4):1693-6. doi: 10.1002/jps.21942, PMID 19774652.

  35. Gajda M, Nartowski KP, Pluta J, Karolewicz B. Continuous, one-step synthesis of pharmaceutical cocrystals via hot melt extrusion from neat to matrix-assisted processing-State of the art. Int J Pharm. 2019 Mar 10;558:426-40. doi: 10.1016/j.ijpharm.2019.01.016, PMID 30664997.

  36. Bidhuri N, Padhi S. Review on comprehensive description of development and assessment of co-crystal drug delivery system. Int J App Pharm. 2023 Sep 07;13:10-6. doi: 10.22159/ijap.2023v15i5.48579.

  37. Przybyłek M, Ziołkowska D, Kobierski M, Mroczyńska K, Cysewski P. Utilization of oriented crystal growth for screening of aromatic carboxylic acids cocrystallization with urea. J Cryst Growth. 2016 Jan 1;433:128-38. doi: 10.1016/j.jcrysgro.2015.10.015.

  38. Urano M, Kitahara M, Kishi K, Goto E, Tagami T, Fukami T. Physical characteristics of cilostazol-hydroxybenzoic acid cocrystals prepared using a spray drying method. Crystals. 2020 Apr 17;10(4):313. doi: 10.3390/cryst10040313.

  39. Yang J, Hong B, Wang N, Li X, Huang X, Bao Y. Thermodynamics and molecular mechanism of the formation of the cocrystals of p -hydroxybenzoic acid and glutaric acid. Cryst Eng Comm. 2019;21(42):6374-81. doi: 10.1039/C9CE01092K.

  40. Ngilirabanga JB, Samsodien H. Pharmaceutical co‐crystal: an alternative strategy for enhanced physicochemical properties and drug synergy. Nano Select. 2021 Mar;2(3):512-26. doi: 10.1002/nano.202000201.

  41. Waterman KC, Waterman AK, Botoy TM, Li J, Qiu F, Hawley M. Stability screening of pharmaceutical cocrystals. Pharm Dev Technol. 2021 Nov 26;26(10):1130-5. doi: 10.1080/10837450.2021.2004607, PMID 34751078.

  42. da Silva CC, Pepino RO, de Melo CC, Tenorio JC, Ellena J. Controlled synthesis of new 5-fluorocytosine cocrystals based on the p K a rule. Cryst Growth Des. 2014 Sep 3;14(9):4383-93. doi: 10.1021/cg500502j.

  43. Duan C, Liu W, Tao Y, Liang F, Chen Y, Xiao X. Two novel palbociclib-resorcinol and palbociclib-orcinol cocrystals with enhanced solubility and dissolution rate. Pharmaceutics. 2021 Dec 23;14(1):23. doi: 10.3390/pharmaceutics14010023, PMID 35056919.

  44. Yu YM, Niu YY, Wang LY, Li YT, Wu ZY, Yan CW. Supramolecular self-assembly and perfected in vitro/vivo property of 5-fluorouracil and ferulic acid on the strength of double optimized strategy: the first 5-fluorouracial-phenolic acid nutraceutical cocrystal with synergistic antitumor efficacy. Analyst. 2021;146(8):2506-19. doi: 10.1039/d1an00171j, PMID 33899060.

  45. Yu YM, Liu L, Bu FZ, Li YT, Yan CW, Wu ZY. A novice cocrystal nanomicelle formulation of 5-fluorouracil with proline: the design, self-assembly and in vitro/vivo biopharmaceutical characteristics. Int J Pharm. 2022 Apr 5;617:121635. doi: 10.1016/j.ijpharm.2022.121635, PMID 35257803.

  46. Zhang Y, Yang R, Yin HM, Zhou B, Hong M, Zhu B. Cocrystals of flavonoids with 4,4′-ethylenebispyridine: crystal structures analysis, dissolution behavior, and anti-tumor activity. J Mol Struct. 2022 Mar 15;1252:132150. doi: 10.1016/j.molstruc.2021.132150.

  47. Jubeen F, Liaqat A, Amjad F, Sultan M, Iqbal SZ, Sajid I. Synthesis of 5-fluorouracil cocrystals with novel organic acids as coformers and anticancer evaluation against HCT-116 colorectal cell lines. Cryst Growth Des. 2020 Feb 10;20(4):2406-14. doi: 10.1021/acs.cgd.9b01570.

  48. Xu LL, Chen JM, Yan Y, Lu TB. Improving the solubility of 6-mercaptopurine via cocrystals and salts. Cryst Growth Des. 2012 Dec 5;12(12):6004-11. doi: 10.1021/cg3010745.

  49. Ren BY, Dai XL, Chen JM, Lu TB. Two anhydrous forms and one monohydrate of a cocrystal of axitinib and glutaric acid: characterization, property evaluation and phase transition study. Cryst Eng Comm. 2022;24(11):2138-48. doi: 10.1039/D1CE01740C.

  50. Anand RA, Nanda AR. Formulation and evaluation of co-crystals of a BCS class II drug using glycine as co-former. Int J Appl Pharm. 2022 Nov 07;14(6):68-76.

  51. Almansa C, Merce R, Tesson N, Farran J, Tomas J, Plata Salaman CR. Co-crystal of tramadol hydrochloride–celecoxib (CTC): a novel API–API co-crystal for the treatment of pain. Cryst Growth Des. 2017 Apr 5;17(4):1884-92. doi: 10.1021/acs.cgd.6b01848.