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Pharmaceutical cocrystals offer a versatile approach to enhancing the properties of drug compounds, making them an important tool in drug formulation and development by improving the therapeutic performance and patient experience of pharmaceutical products. The prediction of cocrystals involves using computational and theoretical methods to identify potential cocrystal formers and understand the interactions between the active pharmaceutical ingredient and coformers. This process aims to predict whether two or more molecules can form a stable cocrystal structure before performing experimental synthesis, thus saving time and resources. In this review, the commonly used cocrystal prediction methods are first overviewed and then evaluated based on three criteria: efficiency, cost-effectiveness, and user-friendliness. Based on these considerations, we suggest to experimental researchers without strong computational experiences which methods and tools should be tested as a first step in the workflow of rational design of cocrystals. However, the optimal choice depends on specific needs and resources, and combining methods from different categories can be a more powerful approach.

Formulating pharmaceutical cocrystals as inhalable dosage forms represents a unique niche in effective management of respiratory infections. Favipiravir, a broad-spectrum antiviral drug with potential pharmacological activity against SARS-CoV-2, exhibits a low aqueous solubility. An ultra-high oral dose is essential, causing low patient compliance. This study reports a Quality-by-Design (QbD)-guided development of a carrier-free inhalable dry powder formulation containing a 1:1 favipiravir–theophylline (FAV-THP) cocrystal via spray drying, which may provide an alternative treatment strategy for individuals with concomitant influenza infections and chronic obstructive pulmonary disease/asthma. The cocrystal formation was confirmed by single crystal X-ray diffraction, powder X-ray diffraction, and the construction of a temperature–composition phase diagram. A three-factor, two-level, full factorial design was employed to produce the optimized formulation and study the impact of critical processing parameters on the resulting median mass aerodynamic diameter (MMAD), fine particle fraction (FPF), and crystallinity of the spray-dried FAV-THP cocrystal. In general, a lower solute concentration and feed pump rate resulted in a smaller MMAD with a higher FPF. The optimized formulation (F1) demonstrated an MMAD of 2.93 μm and an FPF of 79.3%, suitable for deep lung delivery with no in vitro cytotoxicity observed in A549 cells.

The objective of this research was to increase the solubility of Antiretroviral Dolutegravir sodium (DGS), drug by utilizing co-crystallization technique as well formulating Suspension of Dolutegravir sodium cocrystals to enhance the therapeutic effectiveness. Dolutegravir Sodium (DGS) and Salicylic acid cocrystal were created in 1:1 ratio utilizing ethanol as solvent-by-solvent evaporation technique. Developed Cocrystals of Dolutegravir Sodium (DGS) and Salicylic acid assessed for preliminary characterization by utilizing PXRD, DCS, FTIR and SEM. Suspension that contained DGS cocrystals characterized for Dissolution rate, Drug content, Flow rate and Stability study. The findings indicated that the prepared suspension exhibited satisfactory characteristics and remained stable under the testing conditions. In vivo results demonstrate that the tested formulation exhibit quicker absorption compared to the formulation used as control. Hence it can be inferred that Suspension composed of Dolutegravir sodium (DGS) cocrystals shows improved therapeutic performance.

Biopharmaceutics Classification System (BCS) Class II and IV drugs suffer from poor aqueous solubility and hence low bioavailability. Most of these drugs are hydrophobic and cannot be developed into a pharmaceutical formulation due to their poor aqueous solubility. One of the ways to enhance the aqueous solubility of poorlywater-soluble drugs is to use the principles of crystal engineering to formulate cocrystals of these molecules with water-soluble molecules (which are generally called coformers). Many researchers have shown that the cocrystals significantly enhance the aqueous solubility of poorly water-soluble drugs. In this review, we present a consolidated account of reports available in the literature related to the cocrystallization of poorly water-soluble drugs. The current practice to formulate new drug cocrystals with enhanced solubility involves a lot of empiricism. Therefore, in this work, attempts have been made to understand a general framework involved in successful (and unsuccessful) cocrystallization events which can yield different solid forms such as cocrystals, cocrystal polymorphs, cocrystal hydrates/solvates, salts, coamorphous solids, eutectics and solid solutions. The rationale behind screening suitable coformers for cocrystallization has been explained based on the rules of five i.e., hydrogen bonding, halogen bonding (and in general non-covalent bonding), length of carbon chain, molecular recognition points and coformer aqueous solubility. Different techniques to screen coformers for effective cocrystallization and methods to synthesize cocrystals have been discussed. Recent advances in technologies for continuous and solvent-free production of cocrystals have also been discussed. Furthermore, mechanisms involved in solubilization of these solid forms and the parameters influencing dissolution and stability of specific solid forms have been discussed. Overall, this review provides a consolidated account of the rationale for design of cocrystals, past efforts, recent developments and future perspectives for cocrystallization research which will be extremely useful for researchers working in pharmaceutical formulation development.

Cinnamic acid cocrystals have been synthesized with nicotinamide coformers using the solvent evaporation method to produce white crystals. Characterization results with DSC show that cinnamic acid cocrystals have different endothermic peaks of 110°C, cinnamic acid (136°C), and individual nicotinamide (127°C). PXRD results where cinnamic acid cocrystals have different diffractogram patterns with individual cinnamic acid, namely diffractogram peaks at 6.7°, 13.4°, and 20.2°. The FTIR characterization results also indicate that cinnamic acid cocrystals exhibit distinct FTIR spectra. Specifically, there is an absence of twin peaks in the wave number range of 3400-3000 cm-1 corresponding to the -NH group, and absorption peaks resembling fusion appear at wave numbers around 1600 cm-1 and 1500 cm-1, corresponding to -C=O and -C=C alkene groups. Additionally, SEM analysis reveals that while cinnamic acid has an irregular plate-like shape, the formed cocrystals exhibit a smooth surface morphology and an irregular block-like shape. Furthermore, the solubility test demonstrates that the solubility of cinnamic acid increases from 0.57 g/100 ml to 1.09 g/100 ml after cocrystallization, indicating a proportional enhancement in Dissolution Efficiency (DE) from 80.104% to 96.021%. The bond formation in the cocrystal is a hydrogen bond, as indicated by the isosurface map and the RDG Scatter Plot. This bond occurs between the carboxylic group of cinnamic acid and the amide group of nicotinamide in the C=OCA···NICH-N synthon, as well as between the hydroxide group of cinnamic acid and the carboxylic group of nicotinamide in the O-HCA···NICO=C synthon. The hydrogen bond is represented by a blue spike at sign(λ2)ρ around -0.04 a.u.

Cocrystals can be used as an alternative approach based on crystal engineering to enhance specific physicochemical and biopharmaceutical properties of active pharmaceutical ingredients (APIs) when the approaches to salt or polymorph formation do not meet the expected targets. In this article, an overview of pharmaceutical cocrystals will be presented, with an emphasis on the intermolecular interactions in cocrystals and the methods for their preparation. Furthermore, cocrystals of direct pharmaceutical interest, along with their in vitro properties and available in vivo data and characterization techniques are discussed, highlighting the potential of cocrystals as an attractive route for drug development.

Biopharmaceutics Classification System (BCS) Class II and IV drugs suffer from poor aqueous solubility and hence low bioavailability. Most of these drugs are hydrophobic and cannot be developed into a pharmaceutical formulation due to their poor aqueous solubility. One of the ways to enhance the aqueous solubility of poorlywater-soluble drugs is to use the principles of crystal engineering to formulate cocrystals of these molecules with water-soluble molecules (which are generally called coformers). Many researchers have shown that the cocrystals significantly enhance the aqueous solubility of poorly water-soluble drugs. In this review, we present a consolidated account of reports available in the literature related to the cocrystallization of poorly water-soluble drugs. The current practice to formulate new drug cocrystals with enhanced solubility involves a lot of empiricism. Therefore, in this work, attempts have been made to understand a general framework involved in successful (and unsuccessful) cocrystallization events which can yield different solid forms such as cocrystals, cocrystal polymorphs, cocrystal hydrates/solvates, salts, coamorphous solids, eutectics and solid solutions. The rationale behind screening suitable coformers for cocrystallization has been explained based on the rules of five i.e., hydrogen bonding, halogen bonding (and in general non-covalent bonding), length of carbon chain, molecular recognition points and coformer aqueous solubility. Different techniques to screen coformers for effective cocrystallization and methods to synthesize cocrystals have been discussed. Recent advances in technologies for continuous and solvent-free production of cocrystals have also been discussed. Furthermore, mechanisms involved in solubilization of these solid forms and the parameters influencing dissolution and stability of specific solid forms have been discussed. Overall, this review provides a consolidated account of the rationale for design of cocrystals, past efforts, recent developments and future perspectives for cocrystallization research which will be extremely useful for researchers working in pharmaceutical formulation development.

Mechanochemistry is considered an alternative attractive greener approach to prepare diverse molecular compounds and has become an important synthetic tool in different fields (e.g., physics, chemistry, and material science) since is considered an ecofriendly procedure that can be carried out under solvent free conditions or in the presence of minimal quantities of solvent (catalytic amounts). Being able to substitute, in many cases, classical solution reactions often requiring significant amounts of solvents. These sustainable methods have had an enormous impact on a great variety of chemistry fields, including catalysis, organic synthesis, metal complexes formation, preparation of multicomponent pharmaceutical solid forms, etc. In this sense, we are interested in highlighting the advantages of mechanochemical methods on the obtaining of pharmaceutical cocrystals. Hence, in this review, we describe and discuss the relevance of mechanochemical procedures in the formation of multicomponent solid forms focusing on pharmaceutical cocrystals. Additionally, at the end of this paper, we collect a chronological survey of the most representative scientific papers reporting the mechanochemical synthesis of cocrystals.

The most favored approach for drug administration is the oral route. Several anticancer drugs come under this category and mostly lack solubility and oral bioavailability, which are the most common causes of inadequate clinical efficiency. Enhancing oral absorption of anticancer drugs with low aqueous solubility and drug impermeability is currently an effective area of research. Many scientists have looked into pharmaceutical cocrystals as a way to improve the physicochemical properties of several anticancer drugs. Benefits of pharmaceutical cocrystals over other solid forms may include improved solubility, bioavailability, and a reduced susceptibility for phase transition. Cocrystal strategy also stands as a green synthesis tool by using very limited organic solvents during its formulation. Having so many advantages, to date, the reported cocrystals and drug–drug cocrystals of anticancer drugs are limited. Here we review the pharmaceutical cocrystals and drug–drug cocrystals of the anticancer drugs reported in the last decade and their future in imaging, and also shed light on the opportunities and challenges for the development of anticancer drug cocrystals.

Turmeric is a strong-taste component of spices characteristic of Indian cuisine. It is obtained from the turmeric rhizome (Curcumae longae rhizoma) and has been used for thousands of years not only for culinary purposes, but also for medicinal purposes. It contains a group of organic compounds called curcuminoids. Curcumin is the main representative of this group of compounds which is also most frequently studied. In recent years, bioactive curcuminoids (including curcumin in the first place) have become more and more popular due to a wide spectrum of their biological activity. The anticancer, antibacterial, anti-inflammatory, and antiaging effects of curcumin have been confirmed by numerous in vitro and in vivo studies, as well as in clinical trials. However, an obstacle to simple, clinical application of curcumin is its poor bioavailability (which is due to its hydrophobic nature) and its very weak water solubility. Therefore, many scientists are working on improving the solubility of curcumin in water, which is the topic of the present article. Attempts have been made to combine curcumin with nanoparticles (polysaccharide or silica). Nanosuspensions or complexes with cyclodextrins are also considered. A promising direction is the search for new polymorphic varieties as well as obtaining cocrystals with curcumin which are characterized by better water solubility.