Drug Cocrystals Research Articles

Revealing Local Structure of Angiotensin Receptor-Neprilysin Inhibitor (S086) Drug Cocrystal by Linear and Nonlinear Infrared Spectroscopies.

Structurally knowing the active sites of a drug is important for understanding its therapeutic functions. S086 is a novel angiotensin receptor-neprilysin inhibitor that consists of the molecular moieties of EXP3174 (the active metabolite of the angiotensin receptor blocker losartan) and sacubitril (a neprilysin inhibitor prodrug) in a 1:1 molar ratio. There are two forms of cocrystals of S086, namely, ξ-crystal and α-crystal, which were formed both via intermolecular coordination bonding to calcium ions, with the aid of internal water. The binding state of multiple carboxyl anions (COO-) to Ca2+ of EXP3174 and sacubitril was examined in this study using infrared (IR) absorption spectroscopy, in which the asymmetric stretching (as) and symmetric stretching (ss) modes of the COO- groups were used as IR probes. Ultrafast two-dimensional (2D) IR spectroscopy was utilized for spectrally assigning the origin of multiple COO- groups by the presence or absence of interchromophore vibrational coupling. Key structural variation between the two crystal forms was found: in the unit cell of ξ-crystal, the ratio of "bridging" and "bidentate" types of COO- binding to Ca2+ for four EXP3174 molecules is 2:2, while the ratio is predicted to be 3:1 in the case of α-crystal. However, in both crystals, four sacubitril molecules are believed to similarly form a "trident" type of COO- binding to Ca2+. Our study demonstrates that linear and nonlinear IR spectroscopies can be used to characterize local crystal structures of drugs and reveal subtle difference between similar crystal structures.

Preparation and characterization of 5-fluorouracil drug cocrystal and its dynamic monitoring of cocrystallization process via SERS spectroscopy

Cocrystal is a new class of pharmaceutical crystal form, which could improve the physical and chemical properties of drug substance without affecting the internal structure of drug substance. Therefore, the cocrystals show a great deal of potential in the development and research of drugs. 5-Fluorouracil (5-FU) is one of the most widely used anti-pyrimidine drugs. However, its solubility is poor and its oral bioavailability is low. In this work, the cocrystal of 5-FU with nicotinamide was prepared by the solvent evaporation method. The cocrystal structure was confirmed by infrared spectroscopy (IR), X-ray diffraction (XRD) and Raman spectroscopy. The X-ray diffraction and infrared spectroscopy presented that there were significantly different peaks between the raw drug and the cocrystal. Raman spectral results also indicated the differences of such cocrystal compared with the raw drug. In addition, TiN-Ag composite SERS substrate was used to study the formation of 5-FU cocrystal drugs and the formation process was dynamically monitored, and the interaction between molecules during the cocrystal reaction was deeply understood. The cocrystal reaction process was tracked, it can be found that the peak intensity of the raw drug and cocrystal changes with the reaction, indicating that the TiN-Ag composite substrate can monitor the cocrystal transformation process.

Cocrystal Prediction of Nifedipine Based on the Graph Neural Network and Molecular Electrostatic Potential Surface.

Nifedipine (NIF) is a dihydropyridine calcium channel blocker primarily used to treat conditions such as hypertension and angina. However, its low solubility and low bioavailability limit its effectiveness in clinical practice. Here, we developed a cocrystal prediction model based on Graph Neural Networks (CocrystalGNN) for the screening of cocrystals with NIF. And scoring 50 coformers using CocrystalGNN. To validate the reliability of the model, we used another prediction method, Molecular Electrostatic Potential Surface (MEPS), to verify the prediction results. Subsequently, we performed a second validation using experiments. The results indicate that our model achieved high performance. Ultimately, cocrystals of NIF were successfully obtained and all cocrystals exhibited better solubility and dissolution characteristics compared to the parent drug. This study lays a solid foundation for combining virtual prediction with experimental screening to discover novel water-insoluble drug cocrystals.

A drug–drug cocrystal strategy to regulate stability and solubility: A case study of temozolomide/caffeic acid

Temozolomide (TMZ) is a common clinical drug widely used to treat glioblastoma multiforme and gradual astrocytoma. Despite its widespread use in cancer treatment, issues remain with the solubility and stability of TMZ, which can be addressed by synthesizing novel pharmaceutical cocrystals. This study sought to enhance the physiochemical properties of TMZ. To this end, a pioneering pharmaceutical cocrystal of TMZ and caffeic acid (CAF), 2TMZ–CAF·0·5H2O (2:1:0.5) was synthesized and characterized using a solution method. The cocrystal structure was analyzed by molecular surface electrostatic potential (MESP), Hirshfeld surface analysis, and 2D fingerprinting. They were further characterized by single crystal X-ray diffraction, power X-ray diffraction, proton nuclear magnetic resonance, thermogravimetry-differential scanning calorimetry, dynamic vapor sorption, and Fourier transform infrared spectroscopy. Furthermore, the hygroscopicity, stability, and solubility of the TMZ–CAF cocrystal were investigated to evaluate their pharmaceutical applicability. In the asymmetric unit of the novel synthesized cocrystal, two complementary molecules of TMZ and CAF were found, forming planar hydrogen bonding pairs such as O–H···O, N–H···O, and O–H···N. Moreover, the cocrystals exhibited excellent stability compared to TMZ alone and regulated solubility during accelerated stabilization and dissolution processes. Hence, the cocrystals boast characteristics that can circumvent the rapid release of TMZ. In conclusion, the newly synthesized 2TMZ–CAF·0·5H2O cocrystals demonstrate enhanced physiochemical properties, including improved stability and solubility, compared to pure TMZ. This suggests potential utility in drug delivery systems. Additionally, the findings underscore the growing importance of pharmaceutical cocrystals in drug development, with implications for advancing cancer treatment and drug formulation strategies.

Complementary supramolecular drug associates in perfecting the multidrug therapy against multidrug resistant bacteria.

The inappropriate and inconsistent use of antibiotics in combating multidrug-resistant bacteria exacerbates their drug resistance through a few distinct pathways. Firstly, these bacteria can accumulate multiple genes, each conferring resistance to a specific drug, within a single cell. This accumulation usually takes place on resistance plasmids (R). Secondly, multidrug resistance can arise from the heightened expression of genes encoding multidrug efflux pumps, which expel a broad spectrum of drugs from the bacterial cells. Additionally, bacteria can also eliminate or destroy antibiotic molecules by modifying enzymes or cell walls and removing porins. A significant limitation of traditional multidrug therapy lies in its inability to guarantee the simultaneous delivery of various drug molecules to a specific bacterial cell, thereby fostering incremental drug resistance in either of these paths. Consequently, this approach prolongs the treatment duration. Rather than using a biologically unimportant coformer in forming cocrystals, another drug molecule can be selected either for protecting another drug molecule or, can be selected for its complementary activities to kill a bacteria cell synergistically. The development of a multidrug cocrystal not only improves tabletability and plasticity but also enables the simultaneous delivery of multiple drugs to a specific bacterial cell, philosophically perfecting multidrug therapy. By adhering to the fundamental tenets of multidrug therapy, the synergistic effects of these drug molecules can effectively eradicate bacteria, even before they have the chance to develop resistance. This approach has the potential to shorten treatment periods, reduce costs, and mitigate drug resistance. Herein, four hypotheses are presented to create complementary drug cocrystals capable of simultaneously reaching bacterial cells, effectively destroying them before multidrug resistance can develop. The ongoing surge in the development of novel drugs provides another opportunity in the fight against bacteria that are constantly gaining resistance to existing treatments. This endeavour holds the potential to combat a wide array of multidrug-resistant bacteria.

Discovery of new cocrystals beyond serendipity: lessons learned from successes and failures

A holistic understanding of reaction kinetics, the presence of catalysts, and annealing conditions can advance and accelerate the screening of elusive cocrystals, expediting the development of novel drug cocrystals for future clinical use.

Cocrystals of carbamazepine: Structure, mechanical properties, fluorescence properties, solubility, and dissolution rate

Carbamazepine (CBZ) is an anticonvulsant with very low water solubility, presenting as a white crystalline powder with poor mechanical properties and is hard to bend. To enhance CBZ’s physicochemical properties, such as water solubility and mechanical properties, we selected six cocrystal coformers (CCFs): nicotinamide (NIC), benzamide (BZM), salicylic acid (SCA), fumaric acid (FMA), trimesic acid (TMA), and hesperetin (HPE). Six CBZ cocrystals were successfully prepared using the solution method. Fourier transform infrared spectroscopy (FT-IR), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and single crystal X-ray diffraction (SCXRD) were used to characterize the crystal structures and gain comprehensive insights into the six cocrystals. The mechanical, fluorescence, and solubility properties of the six cocrystals were tested. The results reveal that most of the prepared cocrystals exhibit improved water solubility and mechanical properties when compared to CBZ. Among them, the dissolution rate of cocrystals excluded from CBZ-HPE has increased by an average of 3 or 4 times compared to CBZ, while CBZ-HPE exhibits superior mechanical properties. Moreover, all six cocrystals possess better fluorescence performance than CBZ. We thoroughly evaluated the mechanical properties of the cocrystals through both experimental and theoretical approaches. This work provides a new direction for studying drug cocrystals to improve the physicochemical properties of drugs.

A drug–drug cocrystal and a co-amorphous form, prepared from honokiol and ligustrazine, inspired by Chinese patent medicine

A drug–drug cocrystal created with two antithrombotic-active ingredients from herbs, honokiol (HON) and ligustrazine (TMP, 1:1), was synthesized and characterized. The structure of HON–TMP (1:1) was determined by single-crystal X-ray diffraction. Then co-amorphous HON–TMP was prepared by honey-assisted grinding, which was inspired by a grinding process for a Chinese patent medicine-Shijunzi honey pill. This co-amorphous drug–drug cocrystal (20% honey) exhibits improved solubility over HON and a significantly reduced sublimation tendency than TMP.

Control of Dissolution and Supersaturation/Precipitation of Poorly Water-Soluble Drugs from Cocrystals Based on Solubility Products: A Case Study with a Ketoconazole Cocrystal.

This study demonstrates in vitro and in vivo control of cocrystal dissolution with drug supersaturation/precipitation based on the solubility product of a cocrystal. As a cocrystal model, KTZ-4ABA (ketoconazole, KTZ, a poorly water-soluble drug cocrystal, with 4-aminobenzoic acid, 4ABA, a coformer) was used. The presence of 4ABA in the dissolution media dramatically reduced the dissolution rate of KTZ-4ABA and regulated the supersaturation/precipitation of KTZ, supported by the solubility product of KTZ-4ABA. In the in vitro dissolution study, the combined solid form of KTZ-4ABA and a ten-fold amount of 4ABA significantly lowered the degree of KTZ supersaturation without precipitation and further cocrystal dissolution. To confirm cocrystal dissolution control in the gastrointestinal tract with the same composition as the in vitro study, an in vivo oral administration study with rats was conducted. When KTZ was coadministered to rats in the cocrystal form, an excess of 4ABA coadministered with KTZ-4ABA in the solid form reduced the maximum plasma KTZ concentration (Cmax), prolonged the time to reach the Cmax, but did not influence the area under the plasma concentration-time curve. These results demonstrate that both in vitro and in vivo cocrystal dissolution can be regulated by adding an appropriate amount of coformer based on the solubility product, which can be one of the promising strategies for the oral use of cocrystal formulations.

Drug–Drug Cocrystals: A Promising Approach to Overcome Barriers in Pain Management

AbstractPain is one of the critical health issues in the world. While almost everyone experiences acute pain at some point, around 27.5% of the population suffer from its more persistent and chronic form. The current medication regimen is yet to meet expectations and provides suboptimal treatment. Cocrystals are solid forms in which two or more chemically distinct molecules are present in a single crystal lattice. Co‐crystallization offers solutions to the limitations of many drugs in pain treatment. Drug–drug cocrystals (DDC) improve the physicochemical properties of their components and offer a chance to use the synergistic effects of multimodal therapy. DDC have been widely investigated in the field of pain management. Literature on DDC reports improvement in physicochemical properties such as hygroscopicity, solubility, bioavailability, stability, and compressibility. DDC have attracted many researchers, and as a result, a drug product containing cocrystals of tramadol hydrochloride and celecoxib has been successfully commercialized in the United States. Further, one more multidrug cocrystal for pain management has entered advanced clinical trials. This review discusses the applications of DDC in pain management.

A novel drug–drug cocrystal of tegafur and myricetin: optimized properties of dissolution and tabletability

A drug–drug cocrystal of tegafur and myricetin is successfully prepared, which exhibits optimized aqueous solubility and tabletability compared with individual APIs.

Lamotrigine Novel Cocrystals: An Attempt To Enhance Physicochemical Parameters

Background: Cocrystals are defined as multiple component structures whose components interact through non-covalent interactions.Cocrystals can enhance other essential properties of the APIs.Aim: The current research work focuses on formulating and evaluating novel co-crystals of Lamotrigine anti-epileptic drug (BCS-II)Methods: The Cocrystals of Lamotrigine drug with different cocrystals formers like Saccharin sodium, 4-Hydroxy benzoic acid, andMethyl paraben used with molar ratios (1:1) were prepared by solvent drop method, co-grinding method, and solvent evaporationmethod.Results: The results signify the establishment of intermolecular interaction within the cocrystals. In the novel cocrystals, Lamotriginewas determined to be engaged in the hydrogen bond interaction with the complementary functional groups of Saccharin sodium, 4-Hydroxy benzoic acid, and methyl paraben. Compared with the pure Lamotrigine flow properties for prepared co-crystal by usingsolvent evaporation method crystals are showing excellent flow properties. LTG-SAC CF I, LTG-HBA I, and LTG-MP III showed49.6 folds, 7.4 folds, and 3.36 folds improved solubility respectively. The dissolution test showed that the LTG-SAC CF I, LTG-HBAI, and LTG-MP III cocrystals exhibited a 1.09-fold, 1.08-fold, and 1.07-fold higher dissolution rate than the pure Lamotrigine.Conclusions: LTG-SAC CF I, LTG-HBA I, and LTG-MP III cocrystals showed modification in the chemical environment,intermolecular interactions were established, improved flow properties with enhanced intrinsic solubility and in-vitro dissolution ratethan pure drug.

Cocrystals and Drug–Drug Cocrystals of Anticancer Drugs: A Perception towards Screening Techniques, Preparation, and Enhancement of Drug Properties

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.

Preparation of meloxicam-salicylic acid co-crystal and its application in the treatment of rheumatoid arthritis

Meloxicam is a non-steroidal anti-inflammatory drug that can selectively inhibit cyclooxygenase 2 (COX-2), showing high anti-inflammatory activity, low gastrointestinal and renal side effects. However, the low solubility and slow dissolution rate limit its role in rapid pain relief. In this paper, using meloxicam as the active drug molecule and salicylic acid as the co-crystal former, the meloxicam-salicylic acid co-crystal (MLX-SLC CoC) was prepared by the reaction crystallization method. The co-crystal was characterized by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD). The dissolution curve of the co-crystal was determined, and the result showed that the formation of drug co-crystal enhanced the solubility and dissolution rate of MLX. The oil-water partition coefficient of the MLX-SLC CoC was determined, and the results showed that the oil-water partition coefficient of the co-crystal was similar to that of pure MLX. The gel prepared by MLX-SLC CoC was used to study its in vitro release and transdermal penetration characteristics were investigated, which showed that the transdermal penetration of the drug was increased without affecting its in vitro release. Preparation of gel in the form of MLX-SLC CoC increased the drug concentration in the gel. Finally, the therapeutic effect of the gel on arthritis was preliminarily studied by establishing a rheumatoid arthritis rat model.

Crystal Engineering of Pharmaceutical Cocrystals in the Discovery and Development of Improved Drugs.

The subject of crystal engineering started in the 1970s with the study of topochemical reactions in the solid state. A broad chemical definition of crystal engineering was published in 1989, and the supramolecular synthon concept was proposed in 1995 followed by heterosynthons and their potential applications for the design of pharmaceutical cocrystals in 2004. This review traces the development of supramolecular synthons as robust and recurring hydrogen bond patterns for the design and construction of supramolecular architectures, notably, pharmaceutical cocrystals beginning in the early 2000s to the present time. The ability of a cocrystal between an active pharmaceutical ingredient (API) and a pharmaceutically acceptable coformer to systematically tune the physicochemical properties of a drug (i.e., solubility, permeability, hydration, color, compaction, tableting, bioavailability) without changing its molecular structure is the hallmark of the pharmaceutical cocrystals platform, as a bridge between drug discovery and pharmaceutical development. With the design of cocrystals via heterosynthons and prototype case studies to improve drug solubility in place (2000-2015), the period between 2015 to the present time has witnessed the launch of several salt-cocrystal drugs with improved efficacy and high bioavailability. This review on the design, synthesis, and applications of pharmaceutical cocrystals to afford improved drug products and drug substances will interest researchers in crystal engineering, supramolecular chemistry, medicinal chemistry, process development, and pharmaceutical and materials sciences. The scale-up of drug cocrystals and salts using continuous manufacturing technologies provides high-value pharmaceuticals with economic and environmental benefits.

Strategy to Tune the Performance of Two Drug Components: Drug–Drug Cocrystals of Lobaplatin with Flavonoids

Strategy to Tune the Performance of Two Drug Components: Drug–Drug Cocrystals of Lobaplatin with Flavonoids

Cocrystallization of Febuxostat with Pyridine Coformers: Crystal Structural and Physicochemical Properties Analysis

Drug cocrystals and salts have promising applications for modulating the physicochemical properties and solubility of pharmaceuticals. In this study, a cocrystal and two salts of febuxostat (FEB) with pyridine nitrogen coformers, including 4, 4′-bipyridine (BIP), 3-aminopyridine (3AP) and 4-hydroxypyridine (4HP), were designed to improve the solubility of FEB. The single-crystal structures were elucidated, and their physical and chemical properties were investigated by IR, PXRD, and DSC. In addition, drug-related properties, including the solubility and powder dissolution rate were assessed. The solubility and powder dissolution studies showed that the FEB-BIP cocrystal and FEB-3AP salt have superior dissolution compared to FEB.

Mechanochemical synthesis and characterization of a novel AAs–Flucytosine drug–drug cocrystal: A versatile model system for green approaches

Mechanochemistry approach is addressed herein for the green formation of a novel 1:1 drug–drug cocrystal (DDC) involving the antifungal prodrug Flucytosine (5FC) and the non-steroidal anti-inflammatory acetylsalicylic acid (AAS). This DDC was designed considering the huge market demand for new antifungal agents and the antifungal activity reported for some non–steroidal anti–inflammatory drugs, including AAS. The structure-properties characterization of the 5FC-AAS cocrystal was determined by X–ray diffraction (single crystal and powder), differential scanning calorimetry, thermogravimetric analysis, spectroscopic techniques (Raman and Fourier transform infrared), and hot–stage microscopy. The strong O–H…O and N–H…O hydrogen bonds formed between the hydroxyl group of AAS and the carbonyl and amine groups of two symmetry–related 5FC molecules maintain the crystalline packing, together with the same classical R22(8)homodimers observed in other 5FC cocrystals. The direct exposure under accelerated conditions (75% relative humidity/40 °C for 7 days) and at 12–months at room condition were also evaluated. Although the hygroscopicity addressed to 5FC was observed in the cocrystal during the stability studies, nevertheless this property discrepancy can easily be handled with the use of appropriate excipients and packing. DDC production was interestingly achieved by solvent evaporation, neat, and solvent-drop grinding (manually and in a ball-milling), resulting in a very fast production with suitable yield. In this sense, it is believed that this new model DDC will serve as a potential binary base cocrystal system for further developments of related higher dimensional cocrystals in this field, alongside other important drug molecules or in relation to the feasibility of using it therapeutically.

Furosemide/Non-Steroidal Anti-Inflammatory Drug–Drug Pharmaceutical Solids: Novel Opportunities in Drug Formulation

The design of drug–drug multicomponent pharmaceutical solids is one the latest drug development approaches in the pharmaceutical industry. Its purpose is to modulate the physicochemical properties of active pharmaceutical ingredients (APIs), most of them already existing in the market, achieving improved bioavailability properties, especially on oral administration drugs. In this work, our efforts are focused on the mechanochemical synthesis and thorough solid-state characterization of two drug–drug cocrystals involving furosemide and two different non-steroidal anti-inflammatory drugs (NSAIDs) commonly prescribed together: ethenzamide and piroxicam. Besides powder and single crystal X-ray diffraction, infrared spectroscopy and thermal analysis, stability, and solubility tests were performed on the new solid materials. The aim of this work was evaluating the physicochemical properties of such APIs in the new formulation, which revealed a solubility improvement regarding the NSAIDs but not in furosemide. Further studies need to be carried out to evaluate the drug–drug interaction in the novel multicomponent solids, looking for potential novel therapeutic alternatives.

A Drug–Drug Cocrystal of Dihydromyricetin and Pentoxifylline

Drug–drug cocrystals, which can regulate physicochemical properties of individual drugs and might produce synergistic therapeutic effects, have drawn growing interest in the pharmaceutical industry. In this study, a novel drug-drug (1:1) cocrystal hydrate of slightly water-soluble dihydromyricetin (DMY) and highly water-soluble pentoxifylline (PTX), DMY-PTX•H2O (1), was prepared by a slurry method. The single-crystal X-ray diffraction results reveal that the cocrystal is formed through hydrogen-bonding interactions between hydroxyl groups of DMY and four acceptors of PTX. The dynamic vapour sorption results indicate that the cocrystal displays reduced hydrophilicity compared with DMY. It is found that cocrystal formation narrows the solubility difference between two parent drugs. The equilibrium solubility of PTX decreases greatly, while that of DMY increases slightly. As a result, DMY and PTX are synchronously and sustainedly released from the cocrystal. Further, a synergistic anti-cancer effect of the cocrystal DMY-PTX•H2O (1) on HepG2 cells in vitro at a drug concentration of 100 μM was discovered. This study brings evidence of cocrystallization as a successful approach for synchronous sustained-release of two drugs with substantially different aqueous solubility.