Cocrystal Formation Research Articles

Cocrystals Enhance Biopharmaceutical and Antimicrobial Properties of Norfloxacin.

A solvate cocrystal of the antimicrobial norfloxacin (NFX) was formed by using isonicotinamide (INA) as a coformer with the solvent evaporation technique. The cocrystal formation was confirmed by performing solid-state characterization techniques. We evaluated the dissolution under supersaturated conditions and also the solubility at the vertex of triphasic domain of cocrystal and NFX in both water and Fasted-State Simulated Intestinal Fluid (FaSSIF). The antimicrobial activity was evaluated using the microdilution technique. The cocrystal showed 1.8 times higher dissolution than NFX in water at 60 min and 1.3 times higher in FaSSIF at 180 min in the kinetic study. The cocrystal also had an increase in solubility of 8.38 times in water and 6.41 times in FaSSIF. The biopharmaceutical properties of NFX with cocrystallization improved antimicrobial action, as shown in the results of minimum inhibitory concentration (MIC) and inhibitory concentrations of 50% (IC50%) and 90% (IC90%). This paper presents, for the first time, a more in-depth analysis of the cocrystal of NFX-INA concerning its dissolution, solubility, and antimicrobial activity. In all these criteria, the cocrystal obtained better results compared to the pure drug.

Accelerated Wound Healing with a Diminutive Scar through Cocrystal Engineered Curcumin.

Pharmaceutical cocrystals ( Regulatory Classification of Pharmaceutical Co-Crystals Guidance for Industry; Food and Drug Administration, 2018) are crystalline solids produced through supramolecular chemistry to modulate the physicochemical properties of active pharmaceutical ingredients (APIs). Despite their extensive development in interdisciplinary sciences, this is a pioneering study on the efficacy of pharmaceutical cocrystals in wound healing and scar reducing. Curcumin-pyrogallol cocrystal (CUR-PYR) was accordingly cherry-picked since its superior physicochemical properties adequately compensate for limitative drawbacks of curcumin (CUR). CUR-PYR has been synthesized by a liquid-assisted grinding (LAG) method and characterized via FT-IR, DSC, and PXRD analyses. In vitro antibacterial study indicated that CUR-PYR cocrystal, CUR+PYR physical mixture (PM), and PYR are more effective against both Gram-negative (Pseudomonas aeruginosa and Escherichia coli) and Gram-positive (Staphylococcus aureus and Bacillus subtilis) bacteria in comparison with CUR. In vitro results also demonstrated that the viability of HDF and NIH-3T3 cells treated with CUR-PYR were improved more than those received CUR which is attributed to the effect of PYR in the form of cocrystal. The wound healing process has been monitored through a 15 day in vivo experiment on 75 male rats stratified into six groups: five groups treated by CUR-PYR+Vaseline (CUR-PYR.ung), CUR+PYR+Vaseline (CUR+PYR.ung), CUR+Vaseline (CUR.ung), PYR+Vaseline (PYR.ung), and Vaseline (VAS) ointments and a negative control group of 0.9% sodium chloride solution (NS). It was revealed that the wounds under CUR-PYR.ung treatment closed by day 12 postsurgery, while the wounds in other groups failed to reach the complete closure end point until the end of the experiment. Surprisingly, a diminutive scar (3.89 ± 0.97% of initial wound size) was observed in the CUR-PYR.ung treated wounds by day 15 after injury, followed by corresponding values for PYR.ung (12.08 ± 2.75%), CUR+PYR.ung (13.89 ± 5.02%), CUR.ung (16.24 ± 6.39%), VAS (18.97 ± 6.89%), and NS (20.33 ± 5.77%). Besides, investigating histopathological parameters including inflammation, granulation tissue, re-epithelialization, and collagen deposition signified outstandingly higher ability of CUR-PYR cocrystal in wound healing than either of its two constituents separately or their simple PM. It was concluded that desired solubility of the prepared cocrystal was essentially responsible for accelerating wound closure and promoting tissue regeneration which yielded minimal scarring. This prototype research suggests a promising application of pharmaceutical cocrystals for the purpose of wound healing.

Pre-nucleation aggregation of caffeine–benzoic acid as a prediction of co-crystal formation

Pre-nucleation aggregation of caffeine–benzoic acid as a prediction of co-crystal formation

The Role of Crystalline Intermediates in Mechanochemical Cyclorhodation Reactions Elucidated by in-Situ X-ray Powder Diffraction and Computation.

The occurrence of crystalline intermediates in mechanochemical reactions might be more widespread than previously assumed. For example, a recent study involving the acetate-assisted C-H activation of N-Heterocycles with [Cp*RhCl2 ]2 by ball milling revealed the formation of transient cocrystals between the reagents prior to the C-H activation step. However, such crystalline intermediates were only observed through stepwise intervallic ex-situ analysis, and their exact role in the C-H activation process remained unclear. In this study, we monitored the formation of discrete, stoichiometric cocrystals between benzo[h]quinoline and [Cp*RhCl2 ]2 by ball milling using in-situ synchrotron X-ray powder diffraction. This continuous analysis revealed an initial cocrystal that transformed into a second crystalline form. Computational studies showed that differences in noncovalent interactions made the [Cp*RhCl2 ]2 unit in the later-appearing cocrystal more reactive towards NaOAc. This demonstrated the advantage of cocrystal formation before the acetate-assisted metalation-deprotonation step, and how the net cooperative action of weak interactions between the reagents in mechanochemical experiments can lead to stable supramolecular assemblies, which can enhance substrate activation under ball-milling conditions. This could explain the superiority of some mechanochemical reactions, such as acetate-assisted C-H activation, compared to their solution-based counterparts.

Effect of functional group position in co-formers and solvent on cocrystal polymorphism/stoichiomorphism: a case study

In recent years, there has been an increase in the number of reports on cocrystal polymorphism and stoichiomorphism. However, the research on the factors that influence these phenomena is limited. Herein, picolinamide (PAM), nicotinamide (NAM), and isonicotinamide (INA) were selected as co-formers to form multicomponent solids with 4-chloro-3-sulfamoylbenzoic acid (CSBA). Six new cocrystal forms of CSBA were discovered and their crystal structures were determined. It was found that PAM and NAM can only form one cocrystal with CSBA, while INA can form up to four cocrystals, including both cocrystal polymorphism and stoichiomorphism. Molecular electrostatic potential analysis and crystal structure analysis showed that the functional group position of PAM limited the diversity of cocrystal synthons, while the lattice energy limited the diversity of cocrystal synthons when NAM acted as a co-former. Only INA was not subject to these restrictions when forming cocrystals. Finally, the influence of solvents on cocrystals was illustrated by determining the ternary phase diagrams. The mechanism of two similar solvents, ethyl acetate and acetone, controlling the crystallization of cocrystal polymorphism was analyzed by molecular simulations.

Novel Pharmaceutical Cocrystals and Solvate Crystals of Nobiletin, a Citrus Flavonoid with Potent Pharmacological Activity.

Nobiletin (NOB) is a flavonoid with attractive pharmaceutical characteristics, including anti-Alzheimer's, anti-inflammation, and anti-cancer properties, but it has low solubility in water, resulting in reduced bioavailability. Its solubility must be improved to develop NOB as a drug. Cocrystal engineering can change the physicochemical properties of an active pharmaceutical ingredient and generate remarkable drug candidates that are superior in drug formulation. In this report, extensive co-crystal screening of NOBs with 31 cocrystal formers (coformers) with various functional groups was carried out by the liquid-assisted grinding method. As a result, four cocrystals (NOB with urea (URE), oxalic acid, gallic acid and salicylic acid) and one solvate crystal (NOB with formic acid (FOR)) were found. Powder X-ray diffraction and thermal analysis revealed the unique crystal morphology of all the obtained samples. In addition, the crystal structures of two of them (NOB-URE and NOB-FOR) were determined by single crystal X-ray diffraction. The results revealed that NOB-URE and NOB-FOR are new cocrystals or solvate crystals consisting of molar ratios of 1 : 2 and 1 : 0.73, respectively. In NOB-URE, we could observe a transient increase in solubility due to supersaturation, suggesting that URE is one of the better coformers of NOB.

Continuous Manufacturing of Cocrystals Using 3D-Printed Microfluidic Chips Coupled with Spray Coating.

Using cocrystals has emerged as a promising strategy to improve the physicochemical properties of active pharmaceutical ingredients (APIs) by forming a new crystalline phase from two or more components. Particle size and morphology control are key quality attributes for cocrystal medicinal products. The needle-shaped morphology is often considered high-risk and complex in the manufacture of solid dosage forms. Cocrystal particle engineering requires advanced methodologies to ensure high-purity cocrystals with improved solubility and bioavailability and with optimal crystal habit for industrial manufacturing. In this study, 3D-printed microfluidic chips were used to control the cocrystal habit and polymorphism of the sulfadimidine (SDM): 4-aminosalicylic acid (4ASA) cocrystal. The addition of PVP in the aqueous phase during mixing resulted in a high-purity cocrystal (with no traces of the individual components), while it also inhibited the growth of needle-shaped crystals. When mixtures were prepared at the macroscale, PVP was not able to control the crystal habit and impurities of individual mixture components remained, indicating that the microfluidic device allowed for a more homogenous and rapid mixing process controlled by the flow rate and the high surface-to-volume ratios of the microchannels. Continuous manufacturing of SDM:4ASA cocrystals coated on beads was successfully implemented when the microfluidic chip was connected in line to a fluidized bed, allowing cocrystal formulation generation by mixing, coating, and drying in a single step.

Exploring the Crystal Structure Landscape of Sulfasalazine through Various Multicomponent Crystals.

Sulfasalazine is used as an anti-inflammatory drug to treat large intestine diseases and atrophic arthritis. In the solid state, two tautomers are known: an amide tautomer (triclinic polymorph) and an imide tautomer (monoclinic polymorph). Crystallization of six new multicomponent solids of sulfasalazine with three cocrystal formers and three salt formers has been achieved by slurry, liquid-assisted grinding and slow evaporation methods. All of the solid forms are characterized by X-ray diffraction techniques, thermal analysis, and Fourier transform infrared spectroscopy. The crystal structural analysis reveals that two sulfasalazine molecules or anions arrange in a head-to-head fashion involving their pyridyl, amide, and sulfonyl groups in an R22(7):R22(8):R22(7) motif. This is the key structural unit appearing in both sulfasalazine imide polymorph and all six multicomponent crystals. In addition, sulfasalazine exists in the amide form in all unsolvated multicomponent crystals obtained in this work and adopts the imide tautomer in the solvated cocrystals and salt. Hirshfeld surface analysis and the associated two-dimensional (2D) fingerprint plots demonstrate that sulfasalazine has significant hydrogen bond donor capability when cocrystallized and is a significant hydrogen bond acceptor in the salts. The frontier molecular orbital analysis indicates that sulfasalazine cocrystals are chemically more stable than the salts.

Low-Frequency Raman Spectroscopy of Pure and Cocrystallized Mycophenolic Acid.

The aqueous solubility of solid-state pharmaceuticals can often be enhanced by cocrystallization with a coformer to create a binary cocrystal with preferred physical properties. Greater understanding of the internal and external forces that dictate molecular structure and intermolecular packing arrangements enables more efficient design of new cocrystals. Low-frequency (sub-200 cm-1) Raman spectroscopy experiments and solid-state density functional theory simulations have been utilized together to investigate the crystal lattice vibrations of mycophenolic acid, an immunosuppressive drug, in its pure form and as a cocrystal with 2,2'-dipyridylamine. The lattice vibrations primarily consist of large-amplitude translations and rotations of the crystal components, thereby providing insights into the critical intermolecular forces governing cohesion of the molecular solids. The simulations reveal that despite mycophenolic acid having a significantly unfavorable conformation in the cocrystal as compared to the pure solid, the cocrystal exhibits greater thermodynamic stability over a wide temperature range. The energetic penalty due to the conformational strain is more than compensated for by the strong intermolecular forces between the drug and 2,2'-dipyridylamine. Quantifying the balance of internal and external energy factors in cocrystal formation indicates a path forward in the development of future mycophenolic acid cocrystals.

Study on preparation of pillararene cocrystals by liquid-assisted grinding

Liquid-assisted grinding (LAG) has received wide attention in chemical synthesis field. Here, we reported that LAG provides a smart strategy to build macrocyclic cocrystal (MCC), achieving quick modification. The macrocyclic cocrystal has been assembled by electronegative permethylated pillar[5]arenes (EtP5) and electropositive ligands. We select three ligands with strong electron-deficient groups for cocrystal preparation with EtP5 by LAG and judge whether the grinding products are cocrystals by color change, Infrared (IR), Ultraviolet-visible (UV-vis) absorption, and X-ray diffraction (XRD). We demonstrated that the same structure as solvent cocrystal can be obtained by LAG. We obtained the single crystal structure of the EtP5 cocrystal with the promising ligand, confirming the formation of cocrystals and the reliability of the liquid-assisted grinding method.

Acute Pain in Perspective.

Acute pain is a common and nearly universal experience that usually has a sudden onset and is limited in duration. It is a normal physiologic response to a noxious stimulus that can become pathologic if untreated or not treated effectively. Acute pain has a limited duration (<1 month) and often is caused by injury, trauma, or medical treatments such as surgery. Primary care practitioners (PCPs) who encounter patients with acute pain can help preserve function and quality of life and prevent progression to chronic pain by implementing appropriate management strategies. PCPs in rural settings may bear greater responsibility for acute pain management because of the lack of accessible specialists. All current guidelines support using a multimodal approach to pain management and reserving use of opioids for patients with severe pain that cannot be managed with other agents. There are several new agents and formulations recently approved or in development for the treatment of acute pain. The recently approved co-crystal formulation of celecoxib and tramadol hydrochloride provides an additional option for acute pain management and utilizes a single-medication multimodal approach.

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.

Degradants of Tenofovir Disoproxil Fumarate Under Forced Yet Mild Thermal Stress: Isolation, Comprehensive Structural Elucidation, and Mechanism.

In addition to understanding the mechanism of action for a specific drug candidate, information regarding degradation pathways/products under various stress conditions is essential to know about their short- and long-term effects on health and environment. In line with that, tenofovir disoproxil fumarate (TDF, a co-crystal form of the prodrug tenofovir with fumaric acid), particularly used as an antiretroviral drug for treatment of HIV and hepatitis-B among others, is subjected to primarily thermal and other ICH-prescribed forced degradation conditions and their various degradation products are identified. Upon thermal degradation at 60°C for 8h, five different degradants (namely DP-1 to DP-5) are isolated, and their structures are unambiguously confirmed using advanced analytical and spectroscopic techniques including ultra-performance liquid chromatography-mass spectrometry (UPLC-MS), high-resolution mass spectrometry (HRMS), state-of-the-art 1- and 2-dimensional nuclear magnetic resonance (1D and 2D NMR), and Fourier-transform infrared spectroscopic (FT-IR) techniques. Among fully characterized five degradants, two new degradants (DP-2 and DP-4) are identified which can potentially impact the stability of TDF via different pathways. Plausible mechanisms leading to all five thermal degradation products are also proposed including the generation of carcinogenic formaldehydefor some cases. The present systematic structural study especially combining MS and advanced NMR investigations unequivocally confirms the structures of the degradants and opens opportunities for connecting the various degradation pathways especially for the TDF-related pharmaceutical candidates.

Cocrystal formation of niclosamide and urea in supercritical CO2 and impact of cosolvent

A cocrystal of niclosamide and urea was attempted for the first time using a crystallization in supercritical solvent (CSS). Experiments were conducted at 40 °C or 60 °C between 3.3 and 29.4 MPa in CO2. Cocrystal formation showed a dependence on the state of CO2 with no cocrystal formation below the critical point and consistently showed partial conversion above the critical point. The addition of 0.5 mL (2.7–3.5 mol%) cosolvent was found to have significant impact on cocrystal formation at 40 °C and 20 MPa. Addition of 2-propanol increased cocrystal formation by between 50 % and 60 % compared to neat scCO2, while cyclohexane reduced cocrystal formation by between 20 % and 35 %, and water completely hindered cocrystal formation. The impact of hold time, cosolvent, solubility in relation to ternary phase diagrams, and inter- and intra-molecular hydrogen bonding are discussed.

A review Review on Co-Crystals New Approach to Modify the Physicochemical Characteristics of API

The expansion of a novel product is constrained by an active medicinal ingredient's poor solubility in aqueous solutions and limited oral bioavailability. A novel strategy to improve the physicochemical characteristics of the active medicinal ingredient is co-crystal formation. The pharmacological action of the API is unaffected by co-crystallization with pharmaceutically acceptable molecules, although it can enhance the physical characteristics like solubility, stability, and dissolution rate. Cocrystals are multi-component systems comprising active medicinal ingredients that also contain a stoichiometric amount of a coformer that is acceptable to the pharmaceutical industry. The pharmaceutical business has a significant chance to create new medicinal products since producing pharmaceutical co-crystals can enhance a drug's physicochemical qualities.The most major benefit of co-crystals is their ability to produce novel medications with improved solubility, which increases the effectiveness and safety of the treatment. The thermodynamic stability of the co-crystal preparation is the key influencing factor. Co-crystal screening provides information on the chemical composition and connection between the active medicinal ingredient and the coformer. This review discusses the many co-crystal synthesis techniques, including hot-melt extrusion, slurrying, antisolvent, grinding, and spray drying. Here is a quick explanation of the characteriszation methods frequently employed for co-crystals, as well as their uses in medicine. Here are some quick summaries of reported research on co-crystals that were evaluated in order to better grasp the notion of co-crystals.&#x0D;

The pKa rule in light of local mode force constants

The prediction of cocrystal or molecular salt formation from organic acid and base constituents in solution usually relies on the pKa rule, an empirical protocol based on the relative tendencies of the isolated protonated form of the base (BH+) and the isolated acid (HA) to undergo dissociation. The underlying physical rationale for this empirical rule has been missing so far. A promising step forward is to harness local mode force constants as bond strength descriptors to gain insights into the salt/cocrystal assessment. Utilizing the water pKa probe at the ωB97X-D(PCM)/aug-cc-pVTZ level of theory for a test set comprising various pyridine and benzoic acid derivatives, we observe a linear relationship between pKa values and the local mode force constant ka in this proof-of-concept study for the test examples that, according to the literature, form cocrystals or molecular salts. In addition, we propose a new way of assessing those cases where ΔpKa falls within the critical 0-3 range. We conclude with a future perspective on how the novel local force constant descriptor can be applied to large databases in the context of machine learning approaches.

Cocrystal Approach to Modulate the Photoluminescent Properties of a GFP Chromophore Analogue: Role of Halogen/Hydrogen Bonding in Achieving a Wide Range of Solid-State Fluorescence Emissions

Fine-tuning the photophysical properties of fluorescent organic solids is essential to attain multicolor displays and meet the demand for futuristic light-emitting materials. Here, we report the tunable luminescence of a green fluorescent protein (GFP) chromophore analogue, 3,4,5-TIA (A), based on the formation of two-component molecular cocrystals with six different coformers. Coformers selected to synthesize the binary cocrystals include 1,4-diiodotetrafluorobenzene (B), perfluoronaphthalene (C), 1,4-dibromotetrafluorobenzene (D), 2,3,5,6-tetrafluoroterephthalic acid (E), benzene-1,2,4,5-tetracarbonitrile (F), and benzene-1,2,4,5-tetracarboxylic acid (G). Interestingly, the cocrystals A•C and A•F showed molecular crystal polymorphism with a slight variation in fluorescence, revealing an aggregation-induced emission (AIE). A crystal structure analysis showed the interplay of hydrogen bonding, halogen bonding, and aromatic π-stacking interactions in associating neutral solid components in the cocrystal. All of the novel cocrystals displayed a wide range of photoluminescence ranging from blue to dark orange. The time-dependent density functional theory (TD-DFT) calculations indicate the changes in the energy level structures (HOMO to LUMO) in cocrystals that resulted in variations in fluorescence emission. The study aims to further understand the structure–property relationship between molecular arrangement and photoluminescence.

Influence of Alkyl Chain Variation on Cocrystal Formation and Molecular Charge Transfer in DIP:Perylene Diimide Binary Systems

Influence of Alkyl Chain Variation on Cocrystal Formation and Molecular Charge Transfer in DIP:Perylene Diimide Binary Systems

Morphological Changes in Betulin Particles as a Result of Polymorphic Transformations, and Formation of Co-Crystals under Heating

Changes in the morphology of betulin crystals during heating at selected temperatures corresponding to polymorphic transformations were investigated. It was shown that the prismatic crystals of starting betulin form III were converted into needles at 120 °C after water removal, followed by the III→II polymorphic transformation. During further heating up to 180 °C, the whiskers of betulin form I were grown. Experiments on betulin heating in the presence of dicarboxylic acids, adipic or suberic showed that the morphological changes can serve as a test for the formation of cocrystals. According to morphological changes, the formation of cocrystals of betulin with adipic acid under heating was identified. The interaction of adipic acid vapor with the surface of betulin crystals was suggested. In contrast, morphological changes in the mixture of betulin and suberic acid under heating provided only the evidence of polymorphic transformations of the components. The results on cocrystal formation by heating were compared with the preparation of cocrystals by the liquid-assistance grinding method. Despite the fact that polymorphic forms with a high surface area were formed when betulin was heated, dissolution studies showed that the starting betulin polymorph III exhibited the highest dissolution rate in comparison with betulin polymorphs obtained under heating.

Solubility and Scale-Up Potency of Norfloxacin-Urea Co-Crystal Prepared by Ultrasound-Assisted Slurry Co-Crystallization Method

Norfloxacin is an antimicrobial in treating urinary tract infections with low water solubility. This study aims to know the effect of norfloxacin-urea co-crystal formation on the solubility of norfloxacin and the potential for scale-up when prepared by ultrasound-assisted slurry co-crystallization method. Identification of the screening result of the norfloxacin-urea (1 : 1) co-crystal formation by a wet grinding method using an ethanol-acetone (1 : 1) solvent mixture was performed by powder X-ray diffractometer (PXRD). The ultrasound-assisted slurry co-crystallization method was used for co-crystal formation with five-fold the weight of norfloxacin and urea than the wet grinding method. The co-crystal product prepared by the ultrasound-assisted slurry co-crystallization method was observed for its crystal morphology and characterized by PXRD and differential scanning calorimeter (DSC). Solubility and dissolution tests in water and acetate buffer solution pH 4.0 were used to evaluate the physicochemical properties. Identification of co-crystal screening by PXRD revealed the formation of norfloxacin-urea co-crystal. The PXRD pattern of the norfloxacin-urea co-crystal product prepared by the ultrasound-assisted slurry co-crystallization method was similar to the wet grinding method. Norfloxacin-urea co-crystal has a different melting point and crystal morphology from pure norfloxacin and urea. The solubility and dissolution rate of norfloxacin-urea co-crystal was higher in water and not significantly different in acetate buffer solution pH 4.0 compared to pure norfloxacin. This study showed that the norfloxacin-urea co-crystal formation could enhance the solubility of norfloxacin in water and had the potential for scale-up when prepared using the ultrasound-assisted slurry co-crystallization method.