Indomethacin Saccharin Research Articles

Interfacial Cocrystallization Using Oily Phase via Liquid–Liquid Phase Separation

Cocrystals consist of two molecules bonded together in a single crystal lattice giving rise to wide applications including improving solubility of poorly soluble pharmaceuticals. Cocrystallization reaction occurs in the oily phase of liquid–liquid phase separation (LLPS) after it is mixed with coformers. Indomethacin–saccharin cocrystal formation was monitored in situ, and the kinetics of crystallization were determined. The crystallization rates show that the process can be proposed to prevent unwanted oily phase formation during LLPS.

Impact of bile salt on solution-mediated phase transformation of pharmaceutical cocrystals: The importance of coformer release kinetics

Cocrystal engineering has become increasingly prevalent as an efficient and versatile route to overcome solubility limitations and improve the oral bioavailability of poorly soluble drugs. However, the unwanted solution-mediated phase transformation of cocrystals to less soluble parent drugs in the gastrointestinal tract may fail to deliver the drug in the body in a sufficient quantity. This study explores how bile salt sodium taurocholate (STC) affects the dissolution performance of indomethacin-saccharin (IMC-SAC) cocrystals. Fluorescence microscopy was used for in situ monitoring of the phase transformation of IMC-SAC cocrystals in the presence and absence of STC during dissolution. Intrinsic dissolution tests, atomic force microscopy and energy dispersive X-ray spectroscopy revealed that there was a significant relationship between the coformer release rate and the kinetics of the phase transformation of cocrystals. The addition of low-concentration STC in the buffer significantly inhibited the phase transformation of IMC-SAC cocrystals by retarding the release of SAC from cocrystals, leading to enhanced release rates of IMC. A molecular dynamics simulation revealed that preferential adsorption of STC molecules on the cocrystal surface may be responsible for the suppression of drastic release of SAC from the cocrystal lattice, thus preventing a rapid crystallization of IMC at the solid–liquid interface. The presence of STC in the buffer could also prolong the supersaturation of IMC, accounting for the overall improved in vitro and in vivo performance of IMC-SAC cocrystals. This study provides a deeper insight into the mechanisms of solution-mediated phase transformation of cocrystals in the presence of endogenous surfactant, which could also be used as an effective strategy to improve the absorption performance of pharmaceutical cocrystals by minimizing the risk of phase transformation during dissolution.

Formation of Indomethacin-Saccharin Cocrystals during Wet Granulation: Role of Polymeric Excipients.

Formulation of a cocrystal into a solid pharmaceutical dosage form entails numerous processing steps during which there is risk of dissociation. In an effort to reduce the number of unit operations, we have attempted the in situ formation of an indomethacin-saccharin (INDSAC) cocrystal during high-shear wet granulation (HSWG). HSWG of IND (poorly water-soluble drug) and SAC (coformer), with polymers (granulating agents), was carried out using ethanol as the granulation liquid and yielded INDSAC cocrystal granules. Therefore, cocrystal formation and granulation were simultaneously accomplished. Our objectives were to (i) evaluate the influence of polymers on cocrystal formation kinetics during wet granulation and (ii) mechanistically understand the role of polymers in facilitating the cocrystal formation. Polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), and polyethylene oxide (PEO) were chosen to investigate the influence of soluble polymers. The cocrystal formation kinetics was influenced by the polymer (PVP < HPC < PEO) and its concentration. The interaction of the polymer with cocrystal components inhibited the cocrystal formation. Complete cocrystal formation was observed in the presence of PEO, a polymer which does not interact with IND and SAC.

Coprocessing of Pharmaceutical Cocrystals for High Quality and Enhanced Physicochemical Stability

Solid state synthesis of high-quality indomethacin–saccharin cocrystals was achieved using hot melt extrusion. The physical and chemical stability of the formed cocrystals was enhanced through coprocessing with inert excipients at the final kneading zone. For the purposes of the study, the synthesized cocrystals were coprocessed with a crystalline hydrophilic polymer (PEG 6000), an amorphous hydrophilic polymer (hydroxypropylmethyl cellulose, HPMC), and an aluminometasilicate inorganic (Neusilin) excipient. Physiochemical characterization of the suspended cocrystals in the Neusilin and HPMC carriers revealed superior stability and the absence of any interactions between the excipients and the parent cocrystals. In contrast extruded cocrystals that were not suspended in any excipient or coprocessed with PEG 6000 underwent disassociation under accelerated conditions. Surface dissolution analysis demonstrated that Neusilin and PEG 6000 have no effect on the cocrystal dissolution rates (>90%), while HPMC led ...

A novel solubilization technique for poorly soluble drugs through the integration of nanocrystal and cocrystal technologies

The aim of the present study was to develop a novel solubilization technique consisting of a nano-cocrystal suspension by integrating cocrystal and nanocrystal formulation technologies to maximize solubilization over current solubilizing technologies.Monodisperse carbamazepine–saccharin, indomethacin–saccharin, and furosemide–caffeine nano-cocrystal suspensions, as well as a furosemide–cytosine nano-salt suspension, were successfully prepared with particle sizes of less than 300nm by wet milling with the stabilizers hydroxypropyl methylcellulose and sodium dodecyl sulfate. Interestingly, the properties of resultant nano-cocrystal suspensions were dramatically changed depending on the physicochemical and structural properties of the cocrystals. In the formulation optimization, the concentration and ratio of the stabilizers also influenced the zeta potentials and particles sizes of the resultant nano-cocrystal suspensions. Raman spectroscopic analysis revealed that the crystalline structures of the cocrystals were maintained in the nanosuspensions, and were physically stable for at least one month. Furthermore, their dissolution profiles were significantly improved over current solubilization-enabling technologies, nanocrystals, and cocrystals.In the present study, we demonstrated that nano-cocrystal formulations can be a new promising option for solubilization techniques to improve the absorption of poorly soluble drugs, and can expand the development potential of poorly soluble candidates in the pharmaceutical industry.

In Situ Monitoring of Antisolvent Cocrystallization by Combining Near-Infrared and Raman Spectroscopies

In situ monitoring techniques are essential for the control and optimization of the cocrystallization process. In our previous study, we successfully monitored indomethacin–saccharin (IMC–SAC) cocrystallization by antisolvent addition using a method based on near-infrared principal component analysis (NIR–PCA). In this study, a calibration model was developed to predict the solute concentration of the two components. Several samples withdrawn from five sets of experiments were used to develop the calibration model. The actual concentrations of the two components were determined using UV–vis spectroscopy and high performance liquid chromatography (HPLC). The amount of solid-phase material in suspension was calculated from these solute concentration data. Correlations between NIR spectra and solid concentrations were evaluated using partial least-squares (PLS) regression analyses. Reasonably good calibration models with determination coefficients (R2) higher than 0.979 were obtained. Process monitoring was performed using in situ NIR and Raman spectroscopies to predict the concentrations of both IMC and SAC in solution and to identify the solid-phase materials, respectively. The calibration models were deemed suitable, with reasonable accuracy and precision, for in situ concentration monitoring of the antisolvent crystallization of IMC–SAC cocrystals. This combination of NIR and Raman spectroscopies was able to detect the formation and phase transition of the resulting cocrystal.

Combined anti-solvent and cooling method of manufacturing indomethacin–saccharin (IMC–SAC) co-crystal powders

The anti-solvent approach has been demonstrated as one potential industrial method to produce pharmaceutical co-crystal powders with high purity. In this study, we combined the anti-solvent method with cooling to maximize the yield of the solution-based co-crystallization between indomethacin (IMC) and saccharin (SAC). The cooling start time was the key process parameter; other parameters were fixed based on results of preliminary work. Highly pure IMC–SAC co-crystal powders were produced via the combined method, regardless of the cooling start time, and the yield was substantially enhanced. However, some material properties, such as crystallinity and particle size, were affected by the cooling start time; i.e., whether cooling was started before nucleation (pre-nucleation cooling) or after nucleation (post-nucleation cooling). When pre-nucleation cooling was applied, a greater degree of supersaturation led to nucleation of α-IMC and IMC–SAC together. The metastable α-IMC eventually transitioned to stable IMC–SAC co-crystal particles, followed by crystal growth. When post-nucleation cooling was applied, the transient α-IMC was not detected during the entire process.

Real-time co-crystal screening and formation between indomethacin and saccharin via DSC analytical technique or DSC–FTIR microspectroscopy

A tool for quick screening co-crystal formation between indomethacin (IMC) and saccharin (SAC) was attempted using DSC analytical technique or DSC–FTIR microspectroscopy as an accelerated method. The solid-state characterizations of IMC, SAC, and their physical, 30-min ground, or solvent-evaporated mixture, were, respectively, investigated. The DSC data evidences that two endothermic peaks at 154 and 184 °C but one exothermic peak at 158 °C were observed in the DSC curve of the physical mixture of IMC–SAC. The former appeared at 154 °C might be due to the fusion of eutectic mixture, but the latter at 184 °C was corresponded to the melting point of IMC–SAC co-crystal following the exothermic peak at 158 °C. The exothermic peak at 158 °C was due to the induction of molecular interaction of IMC and SAC, leading to IMC–SAC co-crystal formation. This indicates that DSC analytical technique could directly detect the thermal changes of the physical mixture of IMC–SAC to form an IMC–SAC co-crystal. Once the temperature was beyond 154 °C after determination with DSC–FTIR microspectroscopy, several new IR absorption peaks at 3165, 1736, 1684, 1319, 1221, and 1176 cm−1 due to the IMC–SAC co-crystal formation via an intermolecular interaction were simultaneously observed from the thermal-dependent three-dimensional FTIR spectral contour. This one-step DSC–FTIR microspectroscopic system giving thermodynamic and spectroscopic information could easily and directly screen and detect the IMC–SAC co-crystal formation in real time.

Effects of Polymer and Surfactant on the Dissolution and Transformation Profiles of Cocrystals in Aqueous Media

Capturing solubility advantages of cocrystals is of great interest, and thus to understand the mechanism by which different excipients could maintain the supersaturation generated by cocrystals at the course of absorption in aqueous media is essential. To achieve this aim, the impact of different excipients on dissolution behavior of indomethacin–saccharin (IND–SAC) were monitored by measuring the concentrations of cocrystal components in the absence and presence of various concentration of excipients by HPLC, and solid phases were analyzed by differential scanning calorimetry after each experiment and the potential of Raman spectroscopy for monitoring phase transformations in situ was tested. No dissolution advantage was offered by cocrystals in the absence of any solution additive. The polymer and surfactant used in the study increased the solubility of IND but not SAC. This differential solubilization effect is believed to have stabilized the cocrystals for a relevant period for the absorption to take ...

Understanding the Formation of Indomethacin–Saccharin Cocrystals by Anti-Solvent Crystallization

Pharmaceutical cocrystals are a novel drug form with the potential to enhance pharmaceutical properties, including the solubility and dissolution behavior for BCS class II drug substances such as indomethacin (IMC). Recently, we reported that pure indomethacin–saccharin (IMC–SAC) cocrystals were prepared via anti-solvent crystallization. In this study, we investigated the solubility behavior of IMC–SAC cocrystals and individual components in methanol–water cosolvent. Also, the phase solubility diagram (PSD) of the cocrystal was determined to increase our understanding of cocrystallization. The criterion for pure IMC–SAC cocrystal formation was proposed and verified through supporting experiments performed with different concentrations. We also found that Scocrystal and Scocrystal/Sdrug are critical factors for the design of the cocrystallization process via anti-solvent addition. Real-time monitoring of the cocrystallization process was performed using an in-line near-infrared (NIR) system. Principal comp...

Characteristics of indomethacin–saccharin (IMC–SAC) co-crystals prepared by an anti-solvent crystallization process

The creation of co-crystals of various insoluble drug substances has been extensively investigated as a promising approach to improve their pharmaceutical performance. In this study, co-crystal powders of indomethacin and saccharin (IMC–SAC) were prepared by an anti-solvent (water) addition and compared with co-crystals by evaporation method. No successful synthesis of a pharmaceutical co-crystal powder via an anti-solvent approach has been reported.Among solvents examined, methanol was practically the only one that resulted in the formation of highly pure IMC–SAC co-crystal powders by anti-solvent approach. The mechanism of a preferential formation of IMC–SAC co-crystal to IMC was explained with two aspects: phase solubility diagram and solution complexation concept. Accordingly, the anti-solvent approach can be considered as a competitive route for producing pharmaceutical co-crystal powders with acceptable properties.

A portable fiber-optic Raman analyzer for fast real-time screening and identifying cocrystal formation of drug-coformer via grinding process

A portable Raman analyzer with a fiber-optic probe was first used to rapidly screen and identify the cocrystal formation between drug and coformer. Indomethacin (IMC) and anhydrous theophylline (TP) were selected as model drugs, but saccharin (SAC) and anhydrous citric acid (CA) were chosen as model coformers. The cocrystal formation that occurred in the solid-state IMC–SAC or TP–CA system via mechanical grinding process was investigated. Differential scanning calorimetry (DSC) was also used to investigate the possible cocrystal formation. The present study indicates that this new portable fiber-opticRaman spectroscopic technique was an easy and fast “real-time” method to screen and identify the progressive cocrystal formation in solid-state IMC–SAC or TP–CA system in the process of mechanical grinding by inserting the probe directly into the ground mixtures.

PH-Dependent Solubility of Indomethacin–Saccharin and Carbamazepine–Saccharin Cocrystals in Aqueous Media

Cocrystals constitute an important class of pharmaceutical solids for their remarkable ability to modulate solubility and pH dependence of water insoluble drugs. Here we show how cocrystals of indomethacin-saccharin (IND-SAC) and carbamazepine-saccharin (CBZ-SAC) enhance solubility and impart a pH-sensitivity different from that of the drugs. IND-SAC exhibited solubilities 13 to 65 times higher than IND at pH values of 1 to 3, whereas CBZ-SAC exhibited a 2 to 10 times higher solubility than CBZ dihydrate. Cocrystal solubility dependence on pH predicted from mathematical models using cocrystal K(sp), and cocrystal component K(a) values, was in excellent agreement with experimental measurements. The cocrystal solubility increase relative to drug was predicted to reach a limiting value for a cocrystal with two acidic components. This limiting value is determined by the ionization constants of cocrystal components. Eutectic constants are shown to be meaningful indicators of cocrystal solubility and its pH dependence. The two contributions to solubility, cocrystal lattice and solvation, were evaluated by thermal and solubility determinations. The results show that solvation is the main barrier for the aqueous solubility of these drugs and their cocrystals, which are orders of magnitude higher than their lattice barriers. Cocrystal increase in solubility is thus a result of decreasing the solvation barrier compared to that of the drug. This work demonstrates the favorable properties of cocrystals and strategies that facilitate their meaningful characterization.

Powder X-ray diffraction method for the quantification of cocrystals in the crystallization mixture

Context: The solid state purity of cocrystals critically affects their performance. Thus, it is important to accurately quantify the purity of cocrystals in the final crystallization product.Objective: The aim of this study was to develop a powder X-ray diffraction (PXRD) quantification method for investigating the purity of cocrystals. The method developed was employed to study the formation of indomethacin-saccharin (IND-SAC) cocrystals by mechanochemical methods.Materials and methods: Pure IND-SAC cocrystals were geometrically mixed with 1:1 w/w mixture of indomethacin/saccharin in various proportions. An accurately measured amount (550 mg) of the mixture was used for the PXRD measurements. The most intense, non-overlapping, characteristic diffraction peak of IND-SAC was used to construct the calibration curve in the range 0–100% (w/w). This calibration model was validated and used to monitor the formation of IND-SAC cocrystals by liquid-assisted grinding (LAG).Results: The IND-SAC cocrystal calibration curve showed excellent linearity (R2 = 0.9996) over the entire concentration range, displaying limit of detection (LOD) and limit of quantification (LOQ) values of 1.23% (w/w) and 3.74% (w/w), respectively. Validation results showed excellent correlations between actual and predicted concentrations of IND-SAC cocrystals (R2 = 0.9981).Discussion: The accuracy and reliability of the PXRD quantification method depend on the methods of sample preparation and handling. The crystallinity of the IND-SAC cocrystals was higher when larger amounts of methanol were used in the LAG method.Conclusion: The PXRD quantification method is suitable and reliable for verifying the purity of cocrystals in the final crystallization product.

Solubility Behavior and Solution Chemistry of Indomethacin Cocrystals in Organic Solvents

The main objective of this study was to investigate the solubility behavior and solution chemistry of indomethacin–saccharin (IND–SAC) cocrystals in organic media. We also evaluated previously proposed models of cocrystal solubility in organic solvents. In addition, the solubility behavior of IND–SAC cocrystals was compared with that of indomethacin–nicotinamide (IND–NIC) cocrystals using the eutectic constant approach. Phase solubility diagrams of IND–SAC cocrystals in various solvents were generated and the transition concentrations, at which drug and cocrystals are in equilibrium with the solvents, were determined. The solubility of IND–SAC cocrystals was explained by the solubility product and solution complexation. The tested models were found to fit the experimental data and to adequately explain the solubility behavior of the cocrystals. The solution complexation of IND and SAC is negligible in ethyl acetate and low in methanol and ethanol. The IND–NIC cocrystals were more soluble than the IND–SAC ...

Bioavailability of indomethacin-saccharin cocrystals

Pharmaceutical cocrystals are new solid forms with physicochemical properties that appear promising for drug product development. However, the in-vivo bioavailability of cocrystals has rarely been addressed. The cocrystal of indomethacin (IND), a Biopharmaceutical Classification System class II drug, with saccharin (SAC) has been shown to have higher solubility than IND at all pH. In this study, we aimed to evaluate the in-vitro dissolution and in-vivo bioavailability of IND-SAC cocrystals in comparison with IND in a physical mixture and the marketed product Indomee. Scale-up of the cocrystals was undertaken using cooling batch crystallisation without seeding. The chemical and physical purity of the up-scaled material was verified using high-performance liquid chromatography, differential scanning calorimetry and powder X-ray diffraction. The IND-SAC cocrystals and IND plus SAC were mixed with lactose and the formulations were placed into gelatin capsules. In-vitro dissolution studies were then performed using the rotating basket dissolution method. The intrinsic dissolution rate of IND and IND-SAC cocrystals was also determined. Finally, a bioavailability study for the formulations was conducted in beagle dogs. The plasma samples were analysed using high-performance liquid chromatography and the pharmacokinetic data were analysed using standard methodologies. The bulk cocrystals (i.e. scaled-up material) were chemically and physically pure. The in-vitro dissolution rate of the cocrystals was higher than that of IND and similar to that of Indomee at pH 7.4 and pH 1.2. The in-vivo bioavailability of the IND-SAC cocrystals in dogs was significantly higher (ANOVA, P<0.05) than that of IND but not significantly different from Indomee (ANOVA, P>0.05). The study indicates that the improved aqueous solubility of the cocrystals leads to improved bioavailability of IND. Thus, the cocrystals are a viable alternative solid form that can improve the dissolution rate and bioavailability of poorly soluble drugs.

Formation of indomethacin–saccharin cocrystals using supercritical fluid technology

The main objective of the present work is to check the feasibility of supercritical fluid (SCF) technologies in the screening and design of cocrystals (novel crystalline solids). The cocrystal formation tendencies in three different SCF techniques, focusing on distinct supercritical fluid properties – solvent, anti-solvent and atomization enhancer – were investigated. The effect of processing parameters on the cocrystal formation behaviour and particle properties in these techniques was also studied. A recently reported indomethacin–saccharin (IND–SAC) cocrystalline system was our model system. A 1:1 molar ratio of indomethacin (γ-form) and saccharin was used as a starting material. The SCF techniques employed in the study include the CSS technique (cocrystallization with supercritical solvent), the SAS technique (supercritical anti-solvent), and the AAS technique (atomization and anti-solvent). The resulting cocrystalline phase was identified using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform-Raman (FT-Raman). The particle morphologies and size distributions were determined using scanning electron microscopy (SEM) and aerosizer, respectively. The pure IND–SAC cocrystals were obtained from SAS and AAS processes, whilst partial to no cocrystal formation occurred in the CSS process. However, no remarkable differences were observed in terms of cocrystal formation at different processing conditions in SAS and AAS processes. Particles from CSS processes were agglomerated and large, whilst needle-to-block-shaped and spherical particles were obtained from SAS and AAS processes, respectively. The particle size distribution of these particles was 0.2–5 μm. Particulate IND–SAC cocrystals with different morphologies and sizes (nano-to-micron) were produced using supercritical fluid techniques. This work demonstrates the potential of SCF technologies as screening methods for cocrystals with possibilities for particle engineering.

Indomethacin–Saccharin Cocrystal: Design, Synthesis and Preliminary Pharmaceutical Characterization

To design and prepare cocrystals of indomethacin using crystal engineering approaches, with the ultimate objective of improving the physical properties of indomethacin, especially solubility and dissolution rate. Various cocrystal formers, including saccharin, were used in endeavours to obtain indomethacin cocrystals by slow evaporation from a series of solvents. The melting point of crystalline phases was determined. The potential cocrystalline phase was characterized by DSC, IR, Raman and PXRD techniques. The indomethacin-saccharin cocrystal (hereafter IND-SAC cocrystal) structure was determined from single crystal X-ray diffraction data. Pharmaceutically relevant properties such as the dissolution rate and dynamic vapour sorption (DVS) of the IND-SAC cocrystal were evaluated. Solid state and liquid-assisted (solvent-drop) cogrinding methods were also applied to indomethacin and saccharin. The IND-SAC cocrystals were obtained from ethyl acetate. Physical characterization showed that the IND-SAC cocrystal is unique vis-à-vis thermal, spectroscopic and X-ray diffraction properties. The cocrystals were obtained in a 1:1 ratio with a carboxylic acid and imide dimer synthons. The dissolution rate of IND-SAC cocrystal system was considerably faster than that of the stable indomethacin gamma-form. DVS studies indicated that the cocrystals gained less than 0.05% in weight at 98%RH. IND-SAC cocrystal was also obtained by solid state and liquid-assisted cogrinding methods. The IND-SAC cocrystal was formed with a unique and interesting carboxylic acid and imide dimer synthons interconnected by weak N-Hcdots, three dots, centeredO hydrogen bonds. The cocrystals were non-hygroscopic and were associated with a significantly faster dissolution rate than indomethacin (gamma-form).

Pharmaceutical applications of biotechnology: Promise and reality. Editorial overview

The aim of the present study was to develop a novel solubilization technique consisting of a nano-cocrystal suspension by integrating cocrystal and nanocrystal formulation technologies to maximize solubilization over current solubilizing technologies.Monodisperse carbamazepine–saccharin, indomethacin–saccharin, and furosemide–caffeine nano-cocrystal suspensions, as well as a furosemide–cytosine nano-salt suspension, were successfully prepared with particle sizes of less than 300 nm by wet milling with the stabilizers hydroxypropyl methylcellulose and sodium dodecyl sulfate. Interestingly, the properties of resultant nano-cocrystal suspensions were dramatically changed depending on the physicochemical and structural properties of the cocrystals. In the formulation optimization, the concentration and ratio of the stabilizers also influenced the zeta potentials and particles sizes of the resultant nano-cocrystal suspensions. Raman spectroscopic analysis revealed that the crystalline structures of the cocrystals were maintained in the nanosuspensions, and were physically stable for at least one month. Furthermore, their dissolution profiles were significantly improved over current solubilization-enabling technologies, nanocrystals, and cocrystals.In the present study, we demonstrated that nano-cocrystal formulations can be a new promising option for solubilization techniques to improve the absorption of poorly soluble drugs, and can expand the development potential of poorly soluble candidates in the pharmaceutical industry.