Solvent-assisted Grinding Research Articles

Study of Luminescence Phenomena of Tb (III) Containing Fluroquinoline for Application in Optoelectronic Devices.

This study presents a series of six vivid green Tb(III) complexes, denoted by the general formula [Tb(L)3.secondary sensitizers], where L represents 1-cyclopropyl-7-(4-ethylpiperazin-1-yl)-6-fluoro-4-oxoquinoline-3-carboxylic acid and secondary sensitizers consist of heterocyclic N-donor aromatic systems. The synthesis of these complexes were achieved through a solvent-assisted grinding method, and their characterization involved various techniques such as CHN analysis, FTIR, NMR, UV, XRD, and NIR spectroscopy. These analyses confirmed the successful synthesis of complexes with coordination between the quinoline moiety and the metal ion. Photoluminescence studies were conducted in solid and solution phases, revealing excellent luminescence properties. The bright green color emitted by the complexes upon exposure to UV rays was attributed to the hypersensitive 5D4 → 7F5 transition. J-O analysis indicated an asymmetrical coordination environment around in the complexes. Additionally, various radiative properties (Ared, Anred, η, βexp, σs) and band gap values were determined, highlighting the potential applications of these complexes in diverse optoelectronic fields. Chromaticity evaluation demonstrated high color purity in both solid and solution phases. Furthermore, the CCT value identified the solid complexes as a cool light source. Overall, the analyses supported the exceptional luminosity of synthesized complexes, positioning them as promising luminescent materials for a wide range of devices.

Preparation, structure and optical properties of TCNB-based charge-transfer cocrystals

Organic charge transfer cocrystals exhibit interesting properties due to their multi-components synergistic and collective effect. Herein, using 1,2,4,5-tetracyanobenzene (TCNB) as electron acceptor, carbazole (CARB), dibenzothiophene (DBZP) and dibenzofuran (DBZF) as electron donors, three charge transfer cocrystals of CARB-TCNB, DBZP-TCNB and DBZF-TCNB were synthesized by solvent evaporation method and solvent-assisted grinding method. These cocrystals were constructed based on the π–π stacking interactions and CH…N hydrogen bonds and confirmed by the SXRD analysis. The stacking modes are consistent with the model that predicted by molecular electrostatic potential analysis (ESP). The IGM and AIM analyses suggested that the π-π stacking and CH…N hydrogen bonds are weak in nature. The purity and homogeneity of cocrystals and grinding products were verified by PXRD analysis. In addition, the IR, UV–vis absorption and luminescent properties were investigated, and the cocrystals and grinding products exhibited different behaviors from that of their precures. In short, this work not only reports the CT complexes synthesized by liquid- and solid- strategies, but also provides an in-depth understanding of the spectral changes caused by the CT interactions.

Chitosan‑iodine complexes: Preparation, characterization, and antibacterial activity

Bacterial infections have always been a major threat to public health, and the development of effective antibacterial substances from natural polymers is crucial. 2-Aminoisonicotinic acid (AN) was grafted onto chitosan by 1-ethyl-(3-dimethylaminopropyl)carbodiimide-mediated coupling reactions, and then modified chitosan‑iodine (CSAN-I) complexes were prepared by solvent-assisted grinding. The samples were characterized using ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy, Raman spectroscopy, proton nuclear magnetic resonance spectroscopy, and X-ray diffraction, confirming that CSAN-I complexes had been successfully prepared. Thermogravimetric (TG) analysis indicated that the chemical modification of chitosan and iodine complexation reduced the thermal stability; X-ray photoelectron spectroscopy (XPS) analysis revealed that 81 % of the iodine in CSAN-I complex was in the form of triiodide ions. The iodine contents of three CSAN-I complexes (CSAN-I-1, CSAN-I-2 and CSAN-I-3) were 1.59 ± 0.22 %, 3.18 ± 0.26 %, and 5.56 ± 0.41 %, respectively. The antibacterial effects were evaluated in vitro, and the results indicated that CSAN-I complexes had strong antibacterial activities against both E. coli and S. aureus. In particular, CSAN-I-3 exhibited the best antibacterial effect. In addition, CSAN-I-3 was nontoxic to L929 cells with good cytocompatibility. Therefore, CSAN-I complexes can be considered as promising candidates for wound management in clinical applications.

Enhancement of Physicochemical and Pharmacokinetic Characteristics of Ranolazine drug substance using Cocrystalization Technique

Biopharmaceutical Classification System II drug, Ranolazine exhibits pH-dependent solubility and thus shows variable absorption along the gastrointestinal tract. Due to poor aqueous solubility particularly in basic pH, an attempt has been made to improve solubility through the cocrystallization technique. Cocrystals of Ranolazine with Nicotinamide have been synthesized at different molar ratios (1:1, 1:2, 1:3 2:1, and 3:1) through solvent-assisted grinding, slurry preparation, and solvent evaporation method and subsequently characterized by different analytical methodologies. Conformational characterization studies have been performed using techniques like melting point analysis, powder X-ray diffraction, and differential scanning calorimetry. Saturation solubility of Ranolazine alone along with cocrystals prepared in different molar ratios was conducted in water and buffers of different pH (1.2, 4.5, and 6.8) to establish enhancement in solubility. Ranolazine: Nicotinamide 1:2 cocrystals were found to be stable in accelerated and long-term stability conditions. In-vivo study performed in rats to demonstrate enhanced bioavailability. Ranolazine cocrystals with Nicotinamide were shown to have enhanced solubility in basic pH and improved peak plasma concentration, the area under the curve, and relative bioavailability by 2-folds.

A Comparative Assessment of Cocrystal and Amorphous Solid Dispersion Printlets Developed by Hot Melt Extrusion Paired Fused Deposition Modeling for Dissolution Enhancement and Stability of Ibuprofen.

The primary focus of the research is to study the role of cocrystal and amorphous solid dispersion approaches for enhancing solubility and preserving the stability of a poorly soluble drug, i.e., ibuprofen (IBP). First, the solvent-assisted grinding approach determined the optimum molar ratio of the drug and the coformer (nicotinamide (NIC)). Later, the polymeric filaments of cocrystals and amorphous solid dispersions were developed using the hot melt extrusion (HME) process, and the printlets were fabricated using the fused deposition modeling (FDM) additive manufacturing process. In addition, the obtained filaments were also milled and compressed into tablets as reference samples. The formation of cocrystals and amorphous solid dispersions was evaluated and confirmed using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and powder X-ray diffraction (PXRD) analysis. The drug release profiles of 3D printlets with 50% infill were found to be faster and are in line with the release profiles of compressed tablets. In addition, the 3D-printed cocrystal formulation was stable for 6months at accelerated conditions. However, the 3D printlets of amorphous solid dispersions and compressed tablets failed to retain stability attributed to the recrystallization of the drug and loss in tablet mechanical properties. This shows the suitability of a cocrystal platform as a novel approach for developing stable formulations of poorly soluble drug substances over amorphous solid dispersions.

Mechanosynthesis of Stable Salt Hydrates of Allopurinol with Enhanced Dissolution, Diffusion, and Pharmacokinetics.

Allopurinol (ALO) is a medication that treats gout and kidney stones by lowering uric acid synthesis in the blood. The biopharmaceutics classification system (BCS) IV drug exhibits poor aqueous solubility, permeability, and bioavailability. To overcome the bottlenecks of ALO, salts with maleic acid (MLE) and oxalic acid (OXA) were synthesized using the solvent-assisted grinding method. The novel multicomponent solids were characterized by PXRD, DSC, TGA, FT-IR, and SEM images. The crystal structures of these salts with variable stoichiometry were obtained using Rietveld refinement from the high-resolution PXRD data. The proton from the dicarboxylic acid is transferred to the most basic pyrimidine "N" of ALO. The N-H···N hydrogen-bonded ALO homodimer is replaced by the N+-H···O- ionic interactions in ALO-OXA (2:1:0.4) and ALO-MLE (1:1:1) salt hydrates. The organic salts improved solubility and dissolution up to 5-fold and the diffusion permeability up to 12 times compared to the native drug in a luminal pH 6.8 phosphate buffer medium. The salt hydrates were exceptionally stable during storage at 30 ± 5 °C and 75 ± 5% relative humidity. Superior dissolution and diffusion permeability of the ALO-MLE salt resulted in improved pharmacokinetics (peak plasma concentration) that offers a promising solid dosage form with enhanced bioavailability and lower dosage formulation.

Investigating the Effect of Emtricitabine Cocrystals with Aromatic Carboxylic Acids on Solubility and Diffusion Permeability

Emtricitabine (ECB), a nucleoside reverse-transcriptase inhibitor, is commonly used to prevent and treat HIV infection in both adults and children. The drug is categorized as a member of the Biopharmaceutics Classification System (BCS) class I with high solubility and moderate permeability. In continuation of the published research work on ECB cocrystals with para-substituted benzoic acids, multicomponent solid form screening was extended with aromatic carboxylic acids in order to improve the diffusion behavior of the native drug. Solvent-assisted grinding of equimolar ECB and aromatic carboxylic acids resulted in three anhydrous cocrystals with meta-hydroxybenzoic acid (MHB), vanillic acid (VAN), and ferulic acid (FER), in addition to three more cocrystal hydrates with para-methyl benzoic acid (PMB), para-chlorobenzoic acid (PCB), and para-nitrobenzoic acid (PNB). The cocrystals were characterized by single-crystal XRD, powder-XRD, DSC/TGA, and FT-IR spectroscopy. In all three cocrystals, the 2-aminopyrimidine···carboxylic acid heterosynthon was found to be prevalent similar to the reported ECB–benzoic acid cocrystal. In ECB–VAN and ECB–MHB, the ECB hydroxyl group was hydrogen-bonded to the hydroxyl groups of the coformers as well as to the carbonyl groups of other ECB molecules, and in ECB–FER, it was interlinked to the ECB carbonyl moiety only. In the other cocrystal hydrates, the ECB-OH group formed hydrogen bonds with water only. The solubility study in a pH 6.8 phosphate buffer indicated the solubility order of ECB > ECB–MHB > ECB–VAN > ECB–FER; i.e., the cocrystal decreased the solubility of the native drug. The diffusion study of ECB and its cocrystals was carried out using a Franz diffusion cell in a pH 6.8 buffer medium which suggests that ECB cocrystals decreased its diffusion rate compared to its native drug due to reduced concentration gradient/solubility and higher hydrophobic interactions.

Binary to ternary drug-drug molecular adducts of the antihypertensive drug ketanserin (KTS) with advanced physicochemical properties.

Focusing on a reliable supramolecular synthon approach, novel molecular salts of the antihypertensive medication ketanserin (KTS) with aromatic carboxylic acid derivatives (benzoic acid (BA), 2-hydroxybenzoic acid (2-HBA), and 2,5-dihydroxybenzoic acid (2,5-DHBA)) are reported. Binary salts of KTS with the respective salt former were obtained via solvent-assisted grinding followed by solution crystallization. Salt production was confirmed through crystal structure investigations that revealed proton transfer from the carboxylic acid group of the salt former to the piperidine nitrogen atom of KTS. A rigorous investigation of the crystal packing of novel binary salts of KTS inspired the construction of ternary adducts, and a ternary crystalline product was subsequently identified using milrinone (MLN), another cardiotonic drug. According to our knowledge, this is the first instance of a dual-drug ternary co-crystal combining both antihypertensive drugs. In order to evaluate the impacts of co-crystallization on the in vitro release behaviour of binary and ternary adducts, solubility tests for the cocrystal were carried out under a variety of physiological pH conditions. The results indicate that, in contrast to the parent drug and binary adducts, the solubility rate of the ternary adducts is significantly increased. Finally, the stability of the synthesised adduct was evaluated under a range of conditions, including temperature (40 ± 1 °C), humidity (90% ± 5% RH, 25 °C) and various solvents media, and it was established that they have good stability. We anticipate that the present findings will work with a wide range of medication combinations, providing a potential new approach to create multi-drug systems for cardiovascular disease.

Novel Ascorbic Acid Co-Crystal Formulations for Improved Stability.

A series of co-crystals of ascorbic acid were prepared with equimolar amounts of co-crystal formers (CCFs), including isonicotinic acid, nicotinic acid, 3,4-dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid and m-hydroxybenzoic acid, by slow solvent evaporation and solvent-assisted grinding. The co-crystals were characterized by single-crystal X-ray diffraction spectroscopy, powder X-ray diffraction, IR spectroscopy, differential scanning calorimetry and thermogravimetric analysis. Molecular dynamics (MD) simulations further validated the interaction energy and the possible intermolecular hydrogen bonds among VC and CCFs. The co-crystals showed improved stability when exposed to different wavelengths of light, pH and temperatures compared to the free analogue, especially at higher pH (~9) and lower temperature (~4 °C).

Single crystal investigation, Hirshfeld surface and interaction energy framework analyses of structure-directing interactions within two isomorphous Schiff's base multicomponent salts

The two new isomorphous Schiff's base multicomponent salts, 1 and 2, have been synthesized using solvent assisted grinding (SAG) methodology and are characterized using microanalyses, NMR and FTIR spectroscopic studies, DT-TGA thermal analysis, single crystal X-ray diffraction technique. All the isomorphous multicomponent salts displayed a 2D interlocked sheet type molecular packing organized symmetrically with various an-isoenergetic non-covalent interactions amongst which predominant contributions are from O−H···N/N−H···O hydrogen bonding interactions over weaker interactions like π···π stacking, C−H···π, H···H, H···Br, and H···Cl interactions. The quantification of all these inter-/intramolecular interactions justifies their propensities to form the supramolecular assembly. All the interactions are addressed critically by 2D fingerprint plots, 3D Hirshfeld surface analysis, and lattice void calculations are done to identify both the size and shape of a molecule and the region of space not associated with a molecule. Additionally, visualization of 3D topology of molecular packing is elucidated from energy-framework calculations which suggest that the intermolecular contacts formed between participating molecules are principally dispersive in nature with total interaction energy estimated for 2 is −32.1 kJ/mol and 1 is −8.5 kJ/mol.

Crystal structures of cocrystals of 2,7-dihydroxynaphthalene with isoniazid and piracetam.

Cocrystals of 2,7-dihydroxynaphthalene (DHN, or naphthalene-2,7-diol) with isoniazid (pyridine-4-carbohydrazide) (INH), denoted DHN-INH [C10H8O2·C6H7N3O, (I)], and piracetam [2-(2-oxopyrrolidin-1-yl)acetamide] (PIR), denoted DHN-PIR [C10H8O2·C6H10N2O2, (II)], were obtained by the solvent-assisted grinding method and characterized by IR spectroscopy, powder X-ray diffraction and single-crystal X-ray diffraction. Cocrystal (I) crystallized in the triclinic space group P-1 and showed a 2:2 stoichiometry. DHN and INH molecules are connected by O-H...N(pyridine) and O-H...N(hydrazide) hydrogen bonds. Cocrystal (II) crystallized in the space group Pca21 with a 1:1 stoichiometry. DHN and PIR molecules are connected by O-H...O=C hydrogen bonds. The supramolecular architecture of cocrystal (I) showed interlinked supramolecular tapes; meanwhile, in cocrystal (II), interlinked supramolecular sheets were observed.

Ketoprofen-FA Co-crystal: In Vitro and In Vivo Investigation for the Solubility Enhancement of Drug by Design of Expert.

The present piece of research work is framed for improving the solubility of ketoprofen by forming co-crystal using fumaric acid as a coformer. Co-crystal of ketoprofen and fumaric acid was prepared by simple solvent-assisted grinding method, containing drug and coformer as independent variables and solubility and % drug release were assumed to be dependent variables. Differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray diffraction, nuclear magnetic resonance and scanning electron microscopy techniques were used to characterize the preparation of optimized batch of co-crystal and further, evaluated for in vitro and in vivo anti-inflammatory and analgesic activities. Based on results of solubility and dissolution rate studies the formulation showed magnified improvement in both the properties on co-crystallization. The values of Gibbs free energy are negative at all levels of carrier demonstrating spontaneity of the drug solubilization process. The IC50 value of optimized batch of co-crystal formulation and the pure drug was observed as 327.33μg/ml and 556.11μg/ml, respectively, demonstrating that co-crystal formulation possesses more percentage protection against protein denaturation than the drug ketoprofen. In vivo (anti-inflammatory and analgesic) activities revealed that optimized batch of co-crystal formulation delivered a rapid pharmacological response in Wistar rats and albino mice when compared with standard drug.

Cocrystals of Praziquantel with Phenolic Acids: Discovery, Characterization, and Evaluation.

Solvent-assisted grinding (SAG) and solution slow evaporation (SSE) methods are generally used for the preparation of cocrystals. However, even by using the same solvent, active pharmaceutical ingredient (API), and cocrystal coformer (CCF), the cocrystals prepared using the two methods above are sometimes inconsistent. In the present study, in the cocrystal synthesis of praziquantel (PRA) with polyhydroxy phenolic acid, including protocatechuic acid (PA), gallic acid (GA), and ferulic acid (FA), five different cocrystals were prepared using SAG and SSE. Three of the cocrystals prepared using the SAG method have the structural characteristics of carboxylic acid dimer, and two cocrystals prepared using the SSE method formed cocrystal solvates with the structural characteristics of carboxylic acid monomer. For phenolic acids containing only one phenolic hydroxyl group (ferulic acid), when preparing cocrystals with PRA by using SAG and SSE, the same product was obtained. In addition, the weak molecular interactions that were observed in the cocrystal are explained at the molecular level by using theoretical calculation methods. Finally, the in vitro solubility of cocrystals without crystal solvents and in vivo bioavailability of PRA-FA were evaluated to further understand the influence on the physicochemical properties of API for the introduction of CCF.

Crystal structure and characterization of the sulfamethazine-piperidine salt.

Sulfamethazine [N1-(4,6-dimethylpyrimidin-2-yl)sulfanilamide] is an antimicrobial drug that possesses functional groups capable of acting as hydrogen-bond donors and acceptors, which make it a suitable supramolecular building block for the formation of cocrystals and salts. We report here the crystal structure and solid-state characterization of the 1:1 salt piperidinium sulfamethazinate (PPD+·SUL-, C5H12N+·C12H13N4O2S-) (I). The salt was obtained by the solvent-assisted grinding method and was characterized by IR spectroscopy, powder X-ray diffraction, solid-state 13C NMR spectroscopy and thermal analysis [differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA)]. Salt I crystallized in the monoclinic space group P21/n and showed a 1:1 stoichiometry revealing proton transfer from SUL to PPD to form salt I. The PPD+ and SUL- ions are connected by N-H+...O and N-H+...N interactions. The self-assembly of SUL- anions displays the amine-sulfa C(8) motif. The supramolecular architecture of salt I revealed the formation of interconnected supramolecular sheets.

Interplay of Halogen and Hydrogen Bonding through Co-Crystallization in Pharmacologically Active Dihydropyrimidines: Insights from Crystal Structure and Energy Framework.

A solvent-assisted grinding method has been used to prepare co-crystals in substituted dihydropyrimidines (DHPM) that constitutes pharmacologically active compounds. These were characterized using FT-IR, PXRD, and single-crystal X-ray diffraction. In order to explore the possibility of formation of halogen (XB) and hydrogen bonding (HB) synthons in the solid state, co-crystallization attempts of differently substituted DHPM molecules, containing nitro, hydoxy, and chloro substituents, with different co-formers, such as 1,4-diiodo tetrafluorobenzene (1,4 DITFB) and 3-nitrobenzoic acid (3 NBA) were performed. The XB co-crystals (C2aXB, C2bXB, and C2cXB) prefer the formation of C-I⋅⋅⋅O/C-I⋅⋅⋅S XB synthon, whereas the HB co-crystal (C2dHB) is stabilized by N-H⋅⋅⋅O H-bond formation. Hirshfeld surface analysis revealed that the percentage contribution of intermolecular interactions for XB co-crystals prefer equal contribution of XB synthon along with HB synthon. Furthermore, the interaction energy was analyzed using energy frameworks, which suggests that their stability, a combination of electrostatics and dispersion, is enhanced through XB/HB in comparison to the parent DHPMs.

Mechanochemical Synthesis of the Catechol-Theophylline Cocrystal: Spectroscopic Characterization and Molecular Structure

Pharmaceutical cocrystallization offers the possibility to modify the physicochemical and biopharmaceutical properties of active pharmaceutical ingredients. The mechanochemical synthesis and spectroscopic characterization of the catechol-theophylline (CAT-TEO) cocrystal is reported. The cocrystal was prepared by the solvent-assisted grinding method. The ATR-IR spectroscopy study allowed to determine the formation of the cocrystal because the O-H and C=O stretching bands in the CAT-TEO cocrystal were shifted with respect to the starting materials, suggesting the formation of the C=O···H-O hydrogen bond interaction. Infrared spectroscopy also allowed to discard hydration of the cocrystal, and polymorphic transitions of the starting products as a consequence of the mechanochemical grinding. The X-ray powder diffraction and thermal studies confirmed the formation of a new solid phase. In the solid state 13C NMR spectra of the cocrystal, the signals were shifted with respect to the starting products. The 13C NMR chemical shifts of the CAT-TEO cocrystal were simulated by using the gauge including the atomic orbital (GIAO) method. These results showed a good correlation between the experimental and calculated 13C NMR results. Theoretical calculations and natural bonding orbital analysis (NBO) at a B3LYP/6-31G(d,p) level of theory were performed to obtain structural information of the cocrystal.

Physicomechanical, stability, and pharmacokinetic evaluation of aceclofenac dimethyl urea cocrystals.

Poor physicomechanical properties and limited aqueous solubility restrict the bioavailability of aceclofenac when given orally. To improve its above properties, aceclofenac (ACE) was cocrystallized with dimethyl urea (DMU) in 1:2 molar ratio by dry and solvent assisted grinding. The cocrystals were characterized by ATR-FTIR, DSC, and PXRD, and their surface morphology was studied by SEM. There was enhancement in intrinsic dissolution rate (IDR) (~eight- and ~fivefold in cocrystals prepared by solvent assisted grinding (SAG) and solid state grinding (SSG), respectively, in 0.1 N HCl, pH 1.2) and similarly (~3.42-fold and ~1.20-fold in phosphate buffer, pH 7.4) as compared to pure drug. Additionally, mechanical properties were assessed by tabletability curves. The tensile strength of ACE was < 1 MPa in contrast to the cocrystal tensile strength (3.5 MPa) which was ~1.98 times higher at 6000 psi. The tablet formulation of cocrystal by direct compression displayed enhanced dissolution profile (~36% in 0.1 N HCl, pH 1.2, and ~100% in phosphate buffer, pH 7.4) in comparison to physical mixture (~ 30% and ~ 80%) and ACE (~18% and ~50%) after 60 min, respectively. Stability studies of cocrystal tablets for 3 months indicated a stable formulation. Pharmacokinetic studies were performed by using rabbit model. The AUC0-∞ (37.87±1.3 μgh/ml) and Cmax (6.94±2.94 μg/ml) of the selected cocrystal C1 prepared by SAG were significantly enhanced (p < 0.05) and were ~3.43 and ~1.63-fold higher than that of ACE. In conclusion, new cocrystal of ACE-DMU was successfully prepared with improved tabletability, in vitro and in vivo properties.

Preparation of Carbamazepine-Nicotinamide Cocrystal

The focus of this investigation was to prepare the cocrystal of carbamazepine (CBZ) using nicotinamide as a coformer and to compare its different preparation methods. The cocrystal was prepared by grinding, solvent-Assisted grinding and ultrasound-assisted cocrystallization methods. They were characterized by Fourier transform infrared spectroscopy (FT-IR), powder X-ray diffraction (PXRD), and morphology by electron microscopy. In conclusion, ultrasound can be applied as a process intensification parameter along with cooling or slurry cocrystallization to produce pure cocrystals under conditions that might result in crystal mixtures in conventional processes.

Structural features and interactions of new sulfamethazine salt and cocrystal

This study explored cocrystal/salt interactions through solid-state characterization and theoretical computation. A novel pharmaceutical salt and cocrystal of sulfamethazine (SMA), sulfamethazine-dichlofenac acid salt (SMA-DA), and sulfamethazine-piperazine cocrystal (SMA-PZ) were prepared through solvent-assisted grinding and solvent evaporation. The solid-state characterization included powder X-ray diffraction, single crystal X-ray diffraction, differential scanning calorimetry, and infrared spectroscopy. Crystal structure analysis shows that SMA and DA create a 1:1 salt with proton transfer, and SMA and PZ create a 1: 0.5 cocrystal. The difference between salt and cocrystal is presented through solid-state characterization and density functional calculations, including Hirshfeld surface and molecular electrostatic potential surface.

Dual-drug co-crystal synthesis for synergistic in vitro effect of three key first-line antiretroviral drugs

Two pharmaceutical solid state co-crystals EFZA and NEF of two non-nucleoside reverse transcriptase inhibitors (efavirenz, EFV and nevirapine, NVP) and a nucleoside reverse transcriptase inhibitor, zidovudine (AZT) were prepared. Currently, these drugs are essential in various front-line HIV treatment regimens due to their potential in the management of HIV infection. Solid-state principles and solvent-assisted grinding were used for screening of co-crystal preparation. Characterization was carried out using DSC, HSM and TGA, then complimented by FT-IR spectral data and powder X-ray diffraction. HPLC analysis was used for a solubility assays. Both co-crystals indicated different thermal behaviour compared to the individual drug components. Differences in vibrational modes within the spectral region and the unique powder X-ray patterns confirmed the identity of EFZA and NEF as new molecular derivatives. Quantitative studies using HPLC indicated an enhanced solubility of the co-crystals at different pH values compared to the parent compounds; thus making these interesting candidates for future formulation.