Cocrystal Formation Research Articles

Spectroscopic and computational investigations of isostructural phase transitions in urea 4-carboxyanilinium nitrate having trapped disordered-nitrate ions

Urea 4-carboxyanilinium nitrate (U4-CAN) and its functional groups deuterated counterpart dU4-CAN were studied using infrared vibrational spectroscopy and computational analysis. Using the known frequencies of the parent components the infrared vibrational frequencies of U4-CAN and dU4-CAN were assigned. FTIR study was carried out to understand how the intra-and inter-molecular interactions in the parent components are affected by U4-CAN co-crystal formation. U4-CAN undergoes isostructural phase transition at 359.1 K. Hence FTIR spectra of U4-CAN were also recorded at different temperature in the range 293 K to 368 K. The interesting observation seen with temperature dependent spectra was:(i) the spectral band intensity increased with increasing temperature and (ii) the peak position of almost all bands did not change in the entire temperature range studied. This results corroborate with the reported structural data of U4-CAN were in it is found that the structural phase transition is isostructural. Hence the crystal structure in the range 293 K to 368 K has same space group and differ only in few hydrogen bond interactions. In order to carry out various theoretical calculation of U4-CAN, the crystallographically obtained structure at 293 K was optimized by density functional theory (DFT) with B3LYP/6–311 G basis set. The theoretical calculated vibration spectra were similar to the experimentally obtained FTIR data. The fingerprint plot of U4-CAN obtained using CrystalExplorer 21 software indicated that the most prominent interaction corresponds to the short O···H contact. Noncovalent interaction (NCL) study indicated that the U4-CAN complex has steric, van der Waals and hydrogen bond interactions and the NH⋅⋅⋅⋅⋅O hydrogen bond interaction between NH3+/ NH2 moieties and NO3- was the strongest. From QTAIM calculation the strongest hydrogen bond interaction in U4-CAN complex was for NH.....O and NH.....N interactions.

Theoretical investigations on N2H5N5/PDO cocrystal via a first‐principles study

AbstractThe exploration of cyclo‐N5ˉ‐based energetic cocrystals represents a noteworthy avenue within pentazolate chemistry, focusing on leveraging cocrystallization to enhance stability. Recently, a novel cocrystal explosive, N2H5N5/PDO, was developed by combining N2H5N5 with pyrazine 1,4‐dioxide (PDO), exhibiting promising detonation characteristics and reduced sensitivity. This study endeavors to elucidate how the structure and noncovalent interactions impact the performance of N2H5N5/PDO through a first‐principles investigation. The results indicate that the enhanced hydrogen bonding and wave‐like crystal packing structure within the cocrystal effectively bolster its stability compared to N2H5N5. The N···H and O···H interactions, in conjunction with π–π interactions, emerge as critical elements driving cocrystal formation. Compared to the pure N2H5N5, the detonation performance of the cocrystal exhibits a slight decline, albeit with a noticeable reduction in sensitivity.

Rapid Synthesis and Evaluation of Resveratrol-Piperazine Cocrystals by Ultrasound and Microwave Methods.

Resveratrol-piperazine cocrystals have been obtained by ultrasound (US) and microwave-assisted (MW) techniques, using the solution and slurry-based methods, to study the influence of the synthesis method on the resulting cocrystal properties, and scalability of the processes. The potential of these cocrystals is represented by the unique properties of their components, resveratrol, and piperazine, which could be also used in veterinary practice. Resveratrol has antimicrobial, antiviral and anticarcinogenic properties, while piperazine can be used in the treatment of parasitic infections. The influence of ultrasound and microwave-assisted treatment was studied by varying synthesis parameters such as reaction time, temperature, and US or MW power. The main advantage of using these methods is represented by shorter synthesis time compared to conventional methods, resulting in the direct formation of the cocrystals. All samples were obtained in high purity, above 97%. Cocrystal yield correlated positively with ultrasound reaction time, while temperature was not found to influence the microwave synthesis yield up to 50°C, in the case of solution-based methods. MW and US-assisted solution-based methods lead to yields between 52.9 and 68.1%. In the case of the slurry-based method, a minimum reaction time of 5 min leads to the formation of cocrystals with high purity. The resveratrol-piperazine cocrystal's solubility and in vitro antibacterial activity were also evaluated, showing promising results. Ultrasound and microwave-assisted techniques offer a viable alternative for synthesizing resveratrol-piperazine cocrystals with short reaction times, high yield, and purity, suitable for scalable resveratrol-piperazine cocrystals.

Chiral resolution of RS-ofloxacin through a novel diastereomeric cocrystal formation with L-glutamic acid by evaporative crystallization and quantification with capillary electrophoresis

Chiral drugs often exhibit significant differences in pharmacological activity between their enantiomers, highlighting the importance of effective chiral separation to enhance therapeutic efficacy and safety. Despite advances in this field, efficient methods for enantiomer separation remain a critical demand, especially for drugs like RS-Ofloxacin (RS-OFX), a chiral fluoroquinolone antibiotic. For RS-OFX, the S-enantiomer exhibits significantly higher potency—approximately 8–128 times greater—than the racemic mixture. This highlights the need to accurately separate the enantiomers. This study presents a new cocrystallization-based method for the precise and economical chiral separation of RS-OFX using amino acids by utilizing the formation of diastereomeric cocrystals. L-Glutamic acid (L-Glu) was identified as an appropriate coformer during the screening of potential coformers; consequently, diastereomeric cocrystals of R-OFX:L-Glu and S-OFX:L-Glu were successfully obtained. Melting point data, Fourier-Transform Infrared Spectroscopy (FTIR), and Powder X-Ray Diffraction (PXRD) analyses all confirmed the existence of a new solid state, revealing significant modifications in the crystal structure indicative of cocrystal formation. Capillary electrophoresis (CE) was employed to quickly identify the most suitable solvent mixture for the separation of the diastereomeric pair. The diastereomeric cocrystals exhibited distinct solubility profiles in various solvent mixtures, allowing effective chiral separation through evaporative crystallization in methanol:chloroform (50:50, v/v) mixture, yielding 61.82% enantiomeric excess (ee) of the more active S-OFX:L-Glu. The results of this study suggest that the chiral resolution of racemic APIs through diastereomeric cocrystal formation with amino acids has the potential for scalability and adaptability in other APIs. This approach has the potential to be a valuable tool for the pharmaceutical industry in improving the efficiency of producing enantiopure pharmaceuticals.

Cocrystal formulation design of 4-Aminosalicylic acid and isoniazid via spray-drying based on a ternary phase diagram toward simultaneous pulmonary delivery

Cocrystal engineering is a potent strategy for enhancing drug properties, but its application in spray-drying has been limited. Furthermore, concurrently introducing two drugs and realizing simultaneous pharmacological effects at the target site is challenging. This is particularly evident for oral formulations designed for systemic use, but the local administration of drugs at the target site displays the potential to overcome this problem. Herein, we investigated the potential of cocrystallization principles for use in developing dry powder inhaler formulations of anti-tuberculosis drugs. We focused on the formation of cocrystals of 4-aminosalicylic acid (PAS) and isoniazid (INH), which are crucial components of tuberculosis treatment. Via spray-drying, we successfully produced spray-dried particles of PAS-INH that exhibited hydrogen bonding interactions between the molecules. Aerosolization performance evaluation with an Andersen Cascade Impactor (ACI) confirmed the concurrent deposition of both drugs, highlighting the potential of our particle design for use in the co-delivery of PAS-INH. Furthermore, simulated lung dissolution studies using the ACI and Transwell inserts revealed synchronized dissolution patterns, indicating promising prospects for use in effective drug delivery. This innovative approach to tuberculosis therapy has significant implications for improving treatment efficacy and enhancing patient adherence, potentially revolutionizing tuberculosis treatment.

Unveiling spectroscopic behaviour and molecular features (DFT studies) of Exemestane-maleic acid cocrystal as model multicomponent system

The present study aimed to investigate the Exemestane - maleic acid (Ex-Mal) cocrystal using Fourier-transform Raman (FT-Raman), Fourier-transform Infrared (FT-IR), Powder X-ray Diffraction (PXRD) and Differential Scanning Calorimeter (DSC) experimental techniques and quantum chemical calculations. Exemestane (Ex) is an irreversible aromatase inhibitor, clinically used for the treatment of postmenopausal women having primary or advanced breast cancer. Maleic acid (Mal), a dicarboxylic acid is found in many vegetables and fruits and is used as a food additive and sweetener. Solution crystallization of Ex and Mal was done in the generation of Ex-Mal cocrystal (1:1). PXRD and DSC analysis confirmed the successful generation of Ex-Mal Cocrystal. Intermolecular hydrogen bonding (O4-H12···O13 & C8-O3···H36) also suggested the formation of a multi-component system, Ex-Mal cocrystal (1:1), as the respective modes shifted in the vibrational (Raman & IR) spectra of cocrystal than the Ex. Further, the quantum theory of atoms in molecules (QTAIM) has been done to analyze the strength and nature of inter-/intra molecular hydrogen bonding. Natural bond orbital (NBO) analysis was performed to check the stabilization energy of the system. The frontier molecular orbital (FMO) analysis predicted that Ex-Mal cocrystal is more reactive and less stable than Ex. Molecular electrostatic potential (MEP) surface showed that electrophilic (C16-H36)/(O4-H12), and nucleophilic (C8=O3)/(C17=O13) reactive groups in Ex/Mal and Mal/Ex, respectively, neutralized after the formation of Ex-Mal cocrystal, confirming the presence of hydrogen bonding interactions (C16-H36∙∙∙O3=C8) and (C17=O13∙∙∙H12-O4). Molar Refractivity (MR) was calculated to check the drug-likeness behaviours of Ex-mal cocrystal. This study provided a comparison of experimental and theoretical results to understand the hydrogen bonding interactions and structural activity of the system.

Co-crystallization of Hesperidin with different co-formers to enhance solubility, antioxidant and anti-inflammatory activities

Hesperidin (HSP) is a natural flavonoid glycoside with very low aqueous solubility and a slow dissolution rate, limiting its effectiveness. This study aims to address these issues by creating co-crystals of hesperidin with water-soluble small molecules (co-formers) such as L-arginine, glutathione, glycine, and nicotinamide. Using the solvent drop grinding method, we prepared three different molar ratios of hesperidin to co-formers (1:1, 1:3, and 1:5) and conducted in-vitro solubility and dissolution studies. The results demonstrated that the prepared co-crystals exhibited significantly enhanced solubility and dissolution rates compared to untreated hesperidin. Of particular note, the HSP co-crystals formula (HSP: L-arg 1:5) displayed approximately 4.5 times higher dissolution than pure hesperidin. Further analysis using FTIR, powder x-ray diffraction patterns, and DSC thermograms validated the formation of co-crystals between HSP and L-arginine. Additionally, co-crystallization with L-arginine improved the in vitro anti-inflammatory and antioxidant activities of hesperidin compared to the untreated drug. This study highlights the potential of using water-soluble small molecules (co-formers) through co-crystallization to enhance the solubility, dissolution, and biological activities of poorly water-soluble drugs. Furthermore, in vivo studies are crucial to validate these promising results.

Complexes of Zinc-Coordinated Heteroaromatic N-Oxides with Pyrene: Lewis Acid Effects on the Multicenter Donor-Acceptor Bonding.

4-Nitroquinoline-N-oxide (NQO) and 4-nitropyridine-N-oxide (NPO) are important precursors for the synthesis of substituted heterocycles while NQO is a popular model mutagen and carcinogen broadly used in cancer research; intermolecular interactions are critical for their reactions or functioning in vivo. Herein, the effects of the coordination of N-oxide's oxygen atom to Lewis acids on multicenter donor-acceptor bonding were explored via a combination of experimental and computational studies of the complexes of NQO and NPO with a typical π-electron donor, pyrene. Coordination with ZnCl2 increased the positive electrostatic potentials on the surfaces of these π-acceptors and lowered the energy of their LUMO. Analogous effects were observed upon the protonation of the N-oxides' oxygen or bonding with boron trifluoride. The interaction of ZnCl2, NPO, or NQO and pyrene resulted in the formation of dark co-crystals comprising π-stacked Zn-coordinated N-oxides and pyrene similar to that found with protonated or (reported earlier) BF3-bonded N-oxides. Computational studies indicated that the coordination of N-oxides to zinc(II), BF3, or protonation led to the strengthening of the multicenter bonding of the nitro-heterocycle with pyrene, and this effect was related both to the increased electrostatic attraction and molecular-orbital interactions in their complexes.

Conformation, virtual cocrystal screening, synthesis and determination of dipyridamole

Drug development necessitates substantial investments in both human and material resources. In the advanced stages of development, significant solubility challenges frequently emerge, critically influencing a drug's applicability and efficacy. Crystal engineering, particularly through the application of cocrystal technology, presents a novel strategy to address these solubility issues without compromising the drug's effectiveness. However, the success rate of cocrystals formation remains relatively low. This article evaluates the impact of widely used virtual cocrystal screening methods on prediction outcomes, especially in the context of conformational diversity. The study describes the effects of eight dipyridamole (DIP) conformations and 130 cocrystal formers (CCFs) using molecular complementarity and molecular electrostatic potential methods, while the hydrogen bond propensity method did not account for conformations variations. Findings indicate that different DIP conformations lead to variable prediction outcomes in virtual cocrystal screening. Thus, it is crucial consider the conformational states of APIs and CCFs in virtual screenings to enhance prediction accuracy. By comparing virtual screening results with experimental results, this study demonstrated that incorporating conformational considerations can improve cocrystal success rates, minimize experimental workload, and contribute to energy-conservation and emission-reduction. Additionally, this research provides the true positives and true negatives data of DIP's cocrystal, laying the groundwork for further studies.

Supramolecular interactions in cocrystals of benzoic acid derivatives with selective COX-2 inhibitor etoricoxib.

The structures of three 1:1 cocrystal forms of etoricoxib {ETR; systematic name: 5-chloro-2-(6-methylpyridin-3-yl)-3-[4-(methylsulfonyl)phenyl]pyridine, C18H15ClN2O2S} have been synthesized and characterized by single-crystal X-ray diffraction; these are etoricoxib-benzoic acid (1/1), C18H15ClN2O2S·C7H6O2 (ETR-Bz), etoricoxib-4-fluorobenzoic acid (1/1), C18H15ClN2O2S·C7H5FO2 (ETR-PFB), and etoricoxib-4-nitrobenzoic acid (1/1), C18H15ClN2O2S·C7H5NO4 (ETR-PNB). Powder X-ray diffraction and thermal differential scanning calorimetry-thermogravimetry (DSC-TG) techniques were also used to characterize these multicomponent systems. Due to the influence of the corresponding acids, ETR shows different conformations. Furthermore, the energetic contributions of the supramolecular motifs have been established by energy framework studies of the stabilizing interaction forces and are consistent with the thermal stability of the cocrystals.

Computational predictions of cocrystal formation: A benchmark study of 28 assemblies comparing five methods from high-throughput to advanced models.

Cocrystals are assemblies of more than one type of molecule stabilized through noncovalent interactions. They are promising materials for improved drug formulation in which the stability, solubility, or biocompatibility of the active pharmaceutical ingredient (API) is improved by including a coformer. In this work, a range of density functional theory (DFT) and density functional tight binding (DFTB) models are systematically compared for their ability to predict the lattice enthalpy of a broad range of existing pharmaceutically relevant cocrystals. These range from cocrystals containing model compounds 4,4'-bipyridine and oxalic acid to those with the well benchmarked APIs of aspirin and paracetamol, all tested with a large set of alternative coformers. For simple cocrystals, there is a general consensus in lattice enthalpy calculated by the different DFT models. For the cocrystals with API coformers the cocrystals, enthalpy predictions depend strongly on the DFT model. The significantly lighter DFTB models predict unrealistic values of lattice enthalpy even for simple cocrystals.

Organic cocrystals: From high‐performance molecular materials to multi‐functional applications

AbstractAdvancements in organic electronics are propelling the development of new material systems, where organic materials stand out for their unique benefits, including tunability and cost‐effectiveness. Organic single crystals stand out for their ordered structure and reduced defects, enhancing the understanding of the relationship between structure and performance. Organic cocrystal engineering builds upon these foundations, exploring intermolecular interactions within multicomponent‐ordered crystalline materials to combine the inherent advantages of single‐component crystals. However, the path to realizing the full potential of organic cocrystals is fraught with challenges, including structural mismatches, unclear cocrystallization mechanisms, and unpredictable property alterations, which complicate the effective cocrystallization between different molecules. To deepen the understanding of this promising area, this review introduces the mechanism of organic cocrystal formation, the various stacking modes, and different growth techniques, and highlights the advancements in cocrystal engineering for multifunctional applications. The goal is to provide comprehensive guidelines for the cocrystal engineering of high‐performance molecular materials, thereby expanding the applications of organic cocrystals in the fields of optoelectronics, photothermal energy, and energy storage and conversion.

A Comparison Study between Green Synthesis of Microwave Irradiation and Solvent Evaporation Methods in The Formation of p-Methoxycinnamic Acid-Succinic Acid Cocrystals

Cocrystal of p-Methoxycinnamate acid-succinic acid has been produced by microwave irradiation and solvent evaporation methods. Cocrystals are formed using succinic acid as the coformer at a molar ratio of 1:1. The formation of cocrystal can be done by solvent evaporation method and microwave radiation method. Physicochemical properties have been studied by FT-IR, DSC, PXRD, and SEM analysis. The solubility test was carried out with pH 6.8 phosphate buffer at a temperature of 25±0.5°C for 5 hours and the dissolution test was carried out with 900 mL pH 6.8 phosphate buffer at a temperature of 37±0.5°C with the speed of 75 rpm using a paddle-type dissolution test apparatus. The solubility of PMCA has increased its solubility in cocrystals by the solvent evaporation method by 1.19 times and by the microwave radiation method by 1.16 times compared to PMCA. The dissolution rate of the cocrystals of the solvent evaporation method increased by 3.50 times and the cocrystals of the microwave radiation method increased by 2.29 times compared to PMCA.

The supramolecular synthon behavior within cocrystals of pyrazinamide and alkyl dicarboxylic acids: A perspective from terahertz spectroscopy and quantum chemical calculation

Pyrazinamide (PZA) is a widely-used anti-tuberculosis pharmaceutical, but its poor solubility prompts us to optimize pharmaceutical performance. Cocrystallization is a promising technique to improve physiochemical properties of active pharmaceutical ingredient (API) by connecting it with cocrystal former (CCF) via intermolecular interactions. Even though a series of alkyl dicarboxylic acids are employed to form cocrystal structures, systematic understanding on the role of intermolecular interactions is still missing. Therefore, terahertz (THz) spectroscopy and quantum chemical calculation are combined to elucidate the behavior of ubiquitous supramolecular synthons, such as hetero-synthons of acid-pyrazine, acid-amide and homo-synthon of amide-amide, from energy's view. Potential energy is calculated to differentiate the stability within polymorphs of PZA-MA cocrystal and free energy is evaluated to compare the solubility of PZA-CCF cocrystals respectively. With regard to vibrational energy, THz spectral fingerprints are theoretically assigned to specific vibrations and attributed to the flexibility deformation of supramolecular synthons based on oscillation theory, where stretching and twisting modes dominate the collective vibrational behavior. It provides a promising tool to evaluate cocrystal performance from its driving force and insightful guidance to discover new pharmaceutical cocrystals.

Mechanochemical Synthesis of Resveratrol-Piperazine Cocrystals.

The 1:1 resveratrol-piperazine cocrystal was successfully synthesized and scaled-up to 300 g scale with the mechanochemical method, as a result of investigating key process parameters, namely the solvent and the grinding time. The use of water, ethanol or ethanol-water mixtures and reaction times up to 50 min were evaluated relative to the dry grinding process. Cocrystal formation and purity were monitored through X-ray diffraction and calorimetry measurements. The dry grinding resulted in an incomplete cocrystal formation, while the use of water or water-ethanol mixture yielded a monohydrate solid phase. Pure ethanol was found to be the optimal solvent for large-scale cocrystallization, as it delivered cocrystals with high crystallinity and purity after 10-30 min grinding time at the laboratory scale. Notably, a relatively fast reaction time (30-60 min) was sufficient for the completion of cocrystallization at larger scales, using a planetary ball mill and a plant reactor. Also, the obtained cocrystal increases the aqueous solubility of resveratrol by 6%-16% at pH = 6.8. Overall, this study highlights the potential of solvent-assisted mechanochemical synthesis as a promising new approach for the efficient production of pure resveratrol-piperazine cocrystals.

Machine learning approach to predict Hansen solubility parameters of cocrystal coformers via integrating group contribution and COSMO-RS

Hansen Solubility Parameters (HSPs) have been a hot topic on predicting the tendency of pharmaceutical cocrystals formation and cocrystal coformers (CCFs) screening. However, the limitation of such application is the lack of models to accurately predict the values of HSPs for drug CCFs with more structural complexity. Accordingly, three ML (machine learning) models, i.e. ANN (Artificial Neural Network), XGBoostRegressor (Extreme Gradient Boosting Regressor) and LGBMRegressor (Light Gradient Boosting Machine Regressor), were developed for predicting the HSPs on CCFs screening for drugs. The HSPs database for 181 CCFs (containing alcohols, alkenes, aromatics, haloalkanes, amines, ketones, ethers, amides, esters, pharmaceuticals, alkanes, acids, nitroalkanes) were established and classified into the training set (140 compounds) and the test set (41 compounds with various functional polarity and groups, covering solid reagents and solvents). The prediction molecular descriptors were combined from the GC (Group Contribution) methods, the COSMO-RS (the Conductor-like Screening Model for Real Solvents) sigma-moments and energy descriptors. The results showed that ANN and XGBoostRegressor beat out LGBMRegressor in predicting HSPs for CCFs. Finally, SHapley Additive exPlanations (SHAP) was employed to visualize and explain the most important characteristics and effects on predicting HSPs via XGBoostRegressor, indicating that CH3, M2 and MHbdon3 had a significant influence and high contribution to the prediction of δd, δp and δh, respectively. The coupled GC and COSMO-RS strategy had been proven as a promising tool to predict HSPs through XGBoostRegressor for screening, designing, and selecting CCFs for drugs.

REVIEW: POTENCY OF AMIDE DERIVATES AS CO-CRYSTAL FORMERS AND ITS IMPACT ON THE PHYSICOCHEMICAL OF ACTIVE PHARMACEUTICAL INGREDIENTS

Enhancing the physicochemical properties of active pharmaceutical ingredients (APIs) has been achieved by utilizing solid modification through the formation of co-crystals. Co-crystal was formed from active pharmaceutical ingredients and co-crystal former, more commonly called coformers. The occurrence of hydrogen bonds in the formation of co-crystals depends on the presence of groups that act as hydrogen bond donors or acceptors in API. Amide-derived coformers are widely used to form hydrogen bonds with API. This review aims to examine the potential of amide derivates as co-crystal-forming materials (coformers), groups in active pharmaceutical ingredients that can form hydrogen bonds with amide derivates and their impact on the physicochemical properties of API. Initial search results yielded 88 articles. Furthermore, the authors then conducted a screening based on exclusion and inclusion criteria, so that a total of 54 articles were obtained as review material. Data analysis in this journal review was carried out using descriptive analysis. Amide derivates have great potential to be used as co-crystal-forming materials due to the presence of amide or carboxamide groups (-CONH2), which can act as donors as well as acceptors of hydrogen bonds. Most of the amide-derived coformers with aliphatic amide groups, aromatic amides, pyridine carboxamides, and sulfonylcarboxamide form heterosynthon bonds with carboxylic groups on API. However, the formation of homosynthon bonds between amide and amide groups can occur, as in the 5-fluorouracil-urea co-crystal. Most of the amide derivates as coformers can change the physicochemical properties of APIs, especially in increasing the solubility and dissolution rate.

Improving the Solubility and Bioavailability of Progesterone Cocrystals with Selected Carboxylic Acids.

Progesterone (PROG) is a natural steroid hormone with low solubility and high permeability that belongs to biopharmaceutics classification system class II. In this study, novel pharmaceutical cocrystals of PROG were successfully prepared by solvent evaporation or a liquid-assisted grinding process aimed at enhancing its solubility and bioavailability. The cocrystal formers selected based on crystal engineering principles were carboxylic acids, namely, 4-formylbenzeneboronic acid (BBA), isophthalic acid (IPA), and 3-nitrophthalic acid (NPA). The cocrystal structures were characterized using multiple techniques. Single-crystal X-ray diffraction results showed that the carbonyl group, acting as a hydrogen bond acceptor, was pivotal in the cocrystal network formation, with C-H···O interactions further stabilizing the crystals. The cocrystals exhibited improved solubility and dissolution profiles in vitro, with no significant changes in hygroscopicity. The parallel artificial membrane permeability assay (PAMPA) models indicated that the cocrystals retained PROG's high permeability. Pharmacokinetic studies in Sprague-Dawley rats revealed that all cocrystals increased PROG exposure, with AUC(0~∞) values for PROG-BBA, PROG-IPA, and PROG-NPA being 742.59, 1201.72 and 442.67 h·ng·mL-1, respectively. These values are substantially higher compared to free PROG, which had an AUC(0~∞) of 301.48 h·ng·mL-1. Notably, PROG-IPA provided the highest AUC improvement, indicating a significant enhancement in bioavailability. Collectively, the study concludes that the cocrystal approach is a valuable strategy for optimizing the physicochemical properties and oral bioavailability of PROG, with potential implications for the development of other poor water-soluble drugs.

Engineering Lipophilic Aggregation of Adapalene and Adamantane-Based Cocrystals via van der Waals Forces and Hydrogen Bonding.

Lipophilic aggregation using adamantanes is a widely exploited molecular property in medicinal and materials chemistry. Adamantanes are traditionally installed to molecular units via covalent bonds. However, the noncovalent installation of adamantanes has been relatively underexplored and presents the potential to bring properties associated with adamantanes to molecules without affecting their intrinsic properties (e.g., pharmacophores). Here, we systematically study a series of adamantanecarboxylic acids with varying substitution levels of methyl groups and their cocrystals with bipyridines. Specifically, single-crystal X-ray diffraction shows that while the directionality of single-component adamantanes is notably sensitive to changes in methyl substitution, hydrogen-bonded cocrystals with bipyridines show consistent and robust packing due to π-stacking predominance. Our observations are supported by Hirshfeld surface and energy framework analyses. The applicability of cocrystal formation of adamantanes bearing carboxylic acids was used to generate the first cocrystals of adapalene, an adamantane-bearing retinoid used for treating acne vulgaris. We envisage our study to inspire noncovalent (i.e., cocrystal) installation of adamantanes to generate lipophilic aggregation in multicomponent systems.

The Impact of Co-crystal Formation on the Stability of Camylofin Dihydrochloride Immediate Release Tablets

The Impact of Co-crystal Formation on the Stability of Camylofin Dihydrochloride Immediate Release Tablets