Cocrystal Formation Research Articles

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.

First cocrystal of esculetin: Simultaneously optimized in vitro/vivo properties and antioxidant effect

Esculetin (ELT) is one of the best-known and simplest coumarins with powerful natural antioxidant effects but insoluble and difficult to absorb. In order to overcome the problems, cocrystal engineering was first applied to ELT in this paper. Nicotinamide (NAM) was selected as the coformer for its excellent water solubility and potential synergistic antioxidant effect with ELT. The structure of the ELT-NAM cocrystal was successfully prepared and characterized by IR, SCXRD, PXRD, and DSC-TG. Furthermore, the in vitro/vivo properties and antioxidant effects of the cocrystal were adequately studied. The results highlight that the ELT obtained tremendous improvements in water solubility and bioavailability after cocrystal formation. Meanwhile, the synergistic enhancement of ELT with NAM in antioxidant effect was demonstrated by the DPPH assay. Ultimately, the simultaneously optimized in vitro/vivo properties and antioxidant activity of the cocrystal created an improved practical effect of hepatoprotective in rat experiments. The investigation is significant for developing coumarin drugs represented by ELT.

Technique Development in Improving the Solubility of Poorly Water Soluble Drugs (BCS II and IV)

Orally active drugs are currently available on the market. API should have adequate solubility and permeability to enhance its therapeutic efficacy when administered orally and obtain optimum bioavailability. Almost 40% of New Chemical Entities had limited solubility or fell into BCS class II and IV. Our review aims to summarize and discuss the development of methods and characterization for increasing the solubility of poorly aqueous drugs from papers published in Google Scholar, NCBI, Science direct, Researchgate, and MDPI. We checked that the methods used such as solid dispersion, cocrystal formation, and coamorphous can increase the solubility of API which has an impact on increasing bioavailability. The successful formation of solid dispersions, cocrystals and coamorphs can be confirmed by the characterization of PXRD, DSC and SEM. In conclusion, drug solubility is an important aspect of pharmacological effects. Drugs with high solubility can provide fast solubility rates and high bioavailability, reducing the dose administered. Solid dispersion, cocrystals, and coamorphous techniques, have succeeded in increasing the solubility of BCS class II and IV drugs.

Optimisation of Pharmaceutical Cocrystal Dissolution Performance through a Synergistic Precipitation Inhibition

ObjectivesPolymeric excipients play an important role in a cocrystal formulation to act as precipitation inhibitors to maximize the potential. Otherwise, a stable form of the parent drug will be recrystallized on the dissolving cocrystal surface and/or in the bulk solution during the cocrystal dissolution process, negating the solubility advantage. The objectives of this work were to investigate the potential of using combined polymers to maximise the dissolution performance of surface precipitation pharmaceutical cocrystals.MethodsThe dissolution performance of a highly soluble flufenamic acid and nicotinamide (FFA-NIC) cocrystal has been systematically studied with predissolved or powder mixed with a single polymer, including a surface precipitation inhibitor [i.e., copolymer of vinylpyrrolidone (60%) /vinyl acetate (40%) (PVP-VA)] and two bulk precipitation inhibitors [i.e., polyethylene glycol (PEG) and Soluplus (SLP)], or binary polymers combinations.ResultsA single polymer of PVP-VA prevented the FFA surface precipitation for an enhanced dissolution performance of FFA-NIC cocrystal. Unfortunately, it cannot sustain the supersaturated FFA concentration in the bulk solution. A combination of two polymers of PVP-VA and SLP has shown a synergistic inhibition effect to enhance the dissolution advantage of FFA-NIC cocrystal.ConclusionsThe dissolution of a cocrystal with surface precipitation of the parent drug can be described as: i) the cocrystal surface contacting the dissolution medium; ii) the cocrystal surface dissolving; iii) the parent drug precipitation on the dissolving surface; and iv) the parent drug particles redissolving. A combination of two types of polymers can be used to maximise the cocrystal performance in solution.Graphical

From Liquid to Solid: Cocrystallization as an Engineering Tool for the Solidification of Pyruvic Acid

Pyruvic acid is an organic compound used in various fields (e.g., the pharmaceutical, cosmetic, food, and chemical industries) and subject to constantly growing demand. Pyruvic acid is liquid at room temperature, rendering manipulation less straightforward. Furthermore, in the liquid phase, pyruvic acid is air-sensitive. We here present a multi-component crystal engineering strategy to render pyruvic acid solid under ambient conditions, focusing on cocrystallization and salt formation. Out of 73 screened cocrystal and salt formers, eight were found to form novel crystalline forms with pyruvic acid. Four of these were studied in detail, with pyruvic acid stable in a solid phase at temperatures up to 120 °C. These results illustrate the effectiveness of cocrystallization as a tool to convert unstable liquid compounds into stable crystalline solid forms.