Carbamazepine-saccharin Research Articles

Crystallisation parameters effect on the particle size distribution (PSD) of carbamazepine-saccharin (CBZ-SAC) co-crystals in batch cooling crystallisation

The crystallisation parameters effect on the particle size distribution (PSD) of carbamazepine-saccharin (CBZ-SAC) co-crystals in batch cooling crystallisation is presented. The particle size distribution study of CBZ-SAC co-crystals revealed that the multimodal with broad PSD was found for CBZ concentration of 19.14 mg/ml. Meanwhile, the unimodal with broad PSD were observed at CBZ concentration of 17.01 mg/ml and 17.96 mg/Crystal characterisation using differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier transform infrared (FTIR) and optical microscopy confirm the solid formed is CBZ-SAC co-crystal Form I with plate-like crystal morphology.

Comparative Evaluation of the Photostability of Carbamazepine Polymorphs and Cocrystals

Carbamazepine (CBZ), a widely used antiepileptic, is known to be sensitive to light. The aim of this study was to evaluate the photostabilities of three cocrystals of CBZ (CBZ–succinic acid (SUC), CBZ–saccharin (SAC) form I, and CBZ–SAC form II) illuminated with a D65 fluorescent lamp compared with those of the conventional solid forms: CBZ polymorphs (forms I, II, and III). The order of discoloration determined using a colorimetric measurement was almost consistent with that of the degradation rates estimated using Fourier-transform infrared reflection–absorption spectroscopy, and these parameters of CBZ polymorphs increased in the order of form III, form I, and form II. CBZ–SUC and CBZ–SAC form I significantly suppressed the discoloration and degradation of CBZ compared with the raw CBZ, while CBZ–SAC form II facilitated the discoloration and degradation of CBZ. These results were supported by the results from the low-frequency Raman spectroscopy. The molecular mobility estimated using solid-state nuclear magnetic resonance 1H spin–lattice relaxation time strongly correlated with the degradation rate constant, indicating that molecular mobility significantly decreased following the formation of CBZ–SUC and CBZ–SAC form I and resulted in higher photostability. Overall, CBZ–SUC and CBZ–SAC form I are photostable forms and cocrystallization was proven to be an effective approach to improving the photostability of a photolabile drug.

Co-crystal polymorphic control by nanodroplet and electrical confinement

The polymorphic control of the co-crystal carbamazepine–saccharin (CBZ–SAC) metastable form II was achieved by nano-droplet confinement in tandem with droplet surface charging induced by electrospraying the precursor solution.

Effect of crystallization method on the formation of carbamazepine-saccharin co-crystal

Co-crystallization is a method in formulation of drug products which is believed to improve drugs solubility, stability and dissolution rate while maintaining the biological functions of its chemical properties. In this work, the carbamazepine-saccharin (CBZ-SAC) co-crystal formation using varies mol ratio of SAC to CBZ, ethyl acetate and formic acid as a solvent and two methods was studied. The physical characterization of the co-crystal was characterized using x-ray diffraction (XRD) powder and differential scanning calorimetry (DSC). The XRD pattern profile analysis had confirm that the CBZ-SAC co-crystal was successfully formed only in ethyl acetate solvent for both of the screening methods applied. The findings also revealed that two polymorphic forms of CBZ-SAC co-crystal was formed during the study.

Mechanistic Basis of Cocrystal Dissolution Advantage

Current interest in cocrystal development resides in the advantages that the cocrystal may have in solubility and dissolution compared with the parent drug. This work provides a mechanistic analysis and comparison of the dissolution behavior of carbamazepine (CBZ) and its 2 cocrystals, carbamazepine-saccharin (CBZ-SAC) and carbamazepine-salicylic acid (CBZ-SLC) under the influence of pH and micellar solubilization. A simple mathematical equation is derived based on the mass transport analyses to describe the dissolution advantage of cocrystals. The dissolution advantage is the ratio of the cocrystal flux to drug flux and is defined as the solubility advantage (cocrystal to drug solubility ratio) times the diffusivity advantage (cocrystal to drug diffusivity ratio). In this work, the effective diffusivity of CBZ in the presence of surfactant was determined to be different and less than those of the cocrystals. The higher effective diffusivity of drug from the dissolved cocrystals, the diffusivity advantage, can impart a dissolution advantage to cocrystals with lower solubility than the parent drug while still maintaining thermodynamic stability. Dissolution conditions where cocrystals can display both thermodynamic stability and a dissolution advantage can be obtained from the mass transport models, and this information is useful for both cocrystal selection and formulation development.

Kinetics and nucleation mechanism of carbamazepine–saccharin co-crystals in ethanol solution

This study aimed to investigate the metastable zone width (MSZW) and the nucleation order of carbamazepine–saccharin (CBZ–SAC) co-crystals via slow cooling crystallisation, to obtain the kinetic value using Kashchiev–Borissova–Hammond–Roberts (KBHR) technique and to deduce the induction time, the radius of the critical nucleus and the interfacial energy of the CBZ–SAC co-crystals via fast cooling. Slow cooling experiments with cooling/heating rates of 0.8, 0.6, 0.4 and 0.2 °C min−1 were applied to determine the crystallisation and the dissolution temperature of CBZ–SAC co-crystals at SAC:CBZ ratios of (3.5, 3.0, 2.5, 2.0 and 1.0) and CBZ concentrations of 19.14, 17.96, 17.06 and 15.83 mg mL−1. Then, fast cooling experiments were run at CBZ concentration of 17.96 mg mL−1 and SAC:CBZ mole ratio of 2.0. Nucleation kinetics, such as MSZW, nucleation order, nucleation kinetic constant and interfacial energy, was determined and analysed. KBHR method was applied to analyse the kinetics value and compared with isothermal method. The nucleation orders obtained from slow cooling method were in between 1.65 and 4.9, which were within the range for nucleation of organic compounds. The results of KBHR method in determining the kinetic values of CBZ–SAC co-crystals were similar to those of the isothermal method.

Effect of Seed Loading and Temperature of Seeding on Carbamazepine-Saccharin Co-Crystal

Objectives: In pharmaceutical industries, the properties of desired final crystal can be modified by seeding process. Seeding activities depend on seed loading, seed size, seed quality and the temperature of supersaturated solution at the time of seed addition. The effect of amount of seed and temperature of seeding on crystallisation and size distribution of carbamazepine-saccharin (CBZ-SAC) co-crystals have been investigated. Methods/Statistical Analysis: 0.5, 1.0 and 1.5 wt% seeds of constant size were added to the metastable zone width region during cooling crystallisation at seeding temperatures of 38.45, 40.35, 42.25, 44.15 and 46.05 oC. Findings: During the crystallisation process of CBZ-SAC co-crystal, nucleation occurred faster when seeding is close to the super solubility curve which is at the highest supersaturation. Crystal size distribution (CSD) results showed more fine particles formed at 38.45oC seed temperature. On the other hand, nucleation occurred slower when seeding is close to the solubility curve, which is at low supersaturation and therefore resulted in less number of fine particles formed. Application: Nucleation of CBZ-SAC co-crystals can be controlled easily by seeding, in which the addition of seed expedites the crystallisation process by providing the surface area for crystals to grow. The size and characteristic of the desired crystal can be adjusted via seeding application.

Preliminary Study on Operating Parameters toward the Metastable Zone-Width of Carbamazepine Co-Crystal

Objectives: Metastable zone width (MSZW) is a crucial parameter in designing co-crystallization process in order to achieve required crystal habits. The effects of operating parameters toward metastable zone width of carbamazepine-saccharin (CBZ-SAC) co-crystal were studied in this research. Methods/Statistical Analysis: Crystallization study was conducted using cooling crystallization method which involves polythermal method. A 250 ml scale size-reactor was used to study the effects of operating parameters on metastable zone width of CBZ-SAC co-crystal which tested with various mol ratio of SAC/CBZ, concentration of CBZ, cooling and heating rates and stirring speeds. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and optical microscopy were applied to characterize the CBZ-SAC co-crystals. Findings: The results show that MSZW decreases as the mol ratios of SAC/CBZ increases, whilst also decreases with CBZ concentrations, cooling rates and stirring speeds. Application/Improvements: Cooling crystallization process is extensively used in the manufacture of pharmaceutical drugs.

Effect of Seed Loading and Temperature of Seeding on Carbamazepine-Saccharin Co-Crystal

Objectives: In pharmaceutical industries, the properties of desired final crystal can be modified by seeding process. Seeding activities depend on seed loading, seed size, seed quality and the temperature of supersaturated solution at the time of seed addition. The effect of amount of seed and temperature of seeding on crystallisation and size distribution of carbamazepine-saccharin (CBZ-SAC) co-crystals have been investigated. Methods/Statistical Analysis: 0.5, 1.0 and 1.5 wt% seeds of constant size were added to the metastable zone width region during cooling crystallisation at seeding temperatures of 38.45, 40.35, 42.25, 44.15 and 46.05 oC. Findings: During the crystallisation process of CBZ-SAC co-crystal, nucleation occurred faster when seeding is close to the super solubility curve which is at the highest supersaturation. Crystal size distribution (CSD) results showed more fine particles formed at 38.45oC seed temperature. On the other hand, nucleation occurred slower when seeding is close to the solubility curve, which is at low supersaturation and therefore resulted in less number of fine particles formed. Application: Nucleation of CBZ-SAC co-crystals can be controlled easily by seeding, in which the addition of seed expedites the crystallisation process by providing the surface area for crystals to grow. The size and characteristic of the desired crystal can be adjusted via seeding application.

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.

Mechanistic Analysis of Cocrystal Dissolution as a Function of pH and Micellar Solubilization.

The purpose of this work is to provide a mechanistic understanding of the dissolution behavior of cocrystals under the influence of ionization and micellar solubilization. Mass transport models were developed by applying Fick’s law of diffusion to dissolution with simultaneous chemical reactions in the hydrodynamic boundary layer adjacent to the dissolving cocrystal surface to predict the pH at the dissolving solid–liquid interface (i.e., interfacial pH) and the flux of cocrystals. To evaluate the predictive power of these models, dissolution studies of carbamazepine–saccharin (CBZ-SAC) and carbamazepine–salicylic acid (CBZ-SLC) cocrystals were performed at varied pH and surfactant concentrations above the critical stabilization concentration (CSC), where the cocrystals were thermodynamically stable. The findings in this work demonstrate that the pH dependent dissolution behavior of cocrystals with ionizable components is dependent on interfacial pH. This mass transport analysis demonstrates the importance of pH, cocrystal solubility, diffusivity, and micellar solubilization on the dissolution rates of cocrystals.

Role of polymers in solution and tablet-based carbamazepine cocrystal formulations

The aim of this study was to evaluate the influence of three chemically diverse polymers, namely hydroxypropylmethylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG) on the phase transformation of three carbamazepine (CBZ) cocrystals including carbamazepine–nicotinamide (CBZ–NIC), carbamazepine–saccharin (CBZ–SAC) and carbamazepine–cinnamic acid (CBZ–CIN) in solution and tablet-based formulations. Based on the solubility and powder dissolution studies, it is demonstrated that cocrystals can be easily formulated through a simple solution formulation or powder formulation to generate supersaturated concentrations and faster dissolution rates to overcome those drugs with solubility and/or dissolution limited bioavailability. However, a polymer-based CBZ cocrystal tablet formulation has not shown any advantage of an improved CBZ release rate compared with the formulation of CBZ III or physical mixtures of CBZ III and coformers. This is in contrast to the solution behaviours of CBZ cocrystals in the solubility and powder dissolution tests because crystallization of the stable solid form of CBZ dihydrate (CBZ DH) within the tablet has taken place, leading to a reduced drug release rate and incomplete release. The mechanism of a polymer inhibition effect on drug precipitation in solution has been elucidated through investigating the molecular interactions among CBZ, coformers and polymers in solution using infrared spectroscopy. Finally, a formulation strategy has been proposed to capture the significant advantages of cocrystals.

Controlling the polymorphism of carbamazepine-saccharin cocrystals formed during antisolvent cocrystallization using kinetic parameters

The cocrystal approach has been extensively investigated over the last decade as one of the most promising methods toward modifying the dissolution behavior of insoluble drug substances. This study demonstrates that the polymorphism of pharmaceutical cocrystalline powders prepared via antisolvent methods can be controlled using kinetic parameters. A carbamazepine-saccharin (CBZ-SAC) cocrystal was selected as a model drug in this study. This crystal was manufactured through a scaled-up antisolvent process with a total solution volume of 4.5 L. CBZ-SAC cocrystal crystalline powders were synthesized by adding 3 L of water as the antisolvent into 1.5 L of CBZ and SAC in methanol, whereby the antisolvent addition rate and the agitation speed were varied as the principal kinetic parameters. To investigate how cocrystallization proceeds under each condition, periodical sampling was combined with off-line characterization and in-line near-infrared (NIR) measurements to monitor the progress of reaction over the 120-minute process. We found that the creation of form-I was preferred when the addition speed or agitation speed was increased, but a highly pure form-II resulted if kinetic conditions were reversed. These differences in polymorphism can be explained by changes in kinetic characteristics when the process is monitored by NIR. This study is directly applicable to the industrial synthesis of these types of materials, precisely when specific CBZ-SAC cocrystalline polymorphs must be manufactured on a large scale.

Effects of coformers on phase transformation and release profiles of carbamazepine cocrystals in hydroxypropyl methylcellulose based matrix tablets

The aim of this study was to investigate the effects of coformers on phase transformation and release profiles of carbamazepine (CBZ) cocrystals in hydroxypropyl methylcellulose (HPMC) based matrix tablets. It has been found that selection of different coformers of saccharin (SAC) and cinnamic acid (CIN) can affect the stability of CBZ cocrystals in solution, resulting in significant differences in the apparent solubility of CBZ. The dissolution advantage of CBZ–SAC cocrystals can only be shown for a short period during dissolution because of the fast conversion to its dihydrate form (DH). HPMC can partially inhibit the crystallisation of CBZ DH during dissolution of CBZ–SAC cocrystal. However, the increased viscosity of HPMC dissolution medium reduced the dissolution rate of CBZ–SAC cocrystals. Therefore the CBZ–SAC cocrystal formulation did not show any significant advantage in CBZ release rate. In contrast the improved CBZ dissolution rate of CBZ–CIN cocrystal can be realised in both solution and formulation due to its high stability. In conclusion, exploring and understanding the mechanisms of the phase transformation of pharmaceutical cocrystals in aqueous medium for selection of lead cocrystals is the key for success of product development.

Continuous Cocrystallization for Dissolution Rate Optimization of a Poorly Water-Soluble Drug

A continuous manufacturing process, hot melt extrusion (HME), was employed for the development of high quality carbamazepine–saccharin (CBZ–SCH) cocrystals. The produced cocrystals were compared with a prototype prepared by a solvent method. It was found that processing parameters such as temperature, screw speed, and screw configuration were the critical processing parameters. In-line near-infrared analysis demonstrated that cocrystallization takes place gradually during the process along the extruder’s mixing zones. Further characterization of the extruded cocrystals proved that the manufactured highly crystalline cocrystals were similar to the prototype but had improved CBZ dissolution rates. Continuous manufacturing of cocrystals of water-insoluble drugs is a novel and robust approach.

Spherical Crystallization of Carbamazepine/Saccharin Co-Crystals: Selective Agglomeration and Purification through Surface Interactions

Spherical crystallization involves crystallization and simultaneous agglomeration of a crystalline particle using an immiscible phase, which has preferential affinity for the crystal surface. Here, we report application of a spherical crystallization technique to the field of co-crystallization. Carbamazepine/saccharin (CBZ/SAC) co-crystals were generated using reverse antisolvent addition and agglomerated using different bridging liquids. Two crystal forms of CBZ/SAC co-crystals were formed, depending on the levels of supersaturation achieved during processing. The selective agglomeration of co-crystal occurred during the agglomeration stage, depending on the relative interaction between bridging liquid and the crystal surfaces. The computational investigation of isosteric heats of adsorption of the bridging liquids at the prominent crystal surfaces proved to be a useful tool in understanding the surface interactions. The spherical crystallization technique shows opportunity to generate co-crystals and its purification through selective agglomeration.

Multivariate analysis of quaternary carbamazepine–saccharin mixtures by X-ray diffraction and infrared spectroscopy

Co-crystallization brings new opportunities for improving the solubility and dissolution rate of drugs with the chance of finely tuning some relevant chemical–physical properties of mixtures containing bioactive compounds. As co-crystallization process involves several molecular species, which are generally solid at room conditions, its control requires accurate knowledge and monitoring of the different phase that might appear during the formulation stage. In the present study the suitability of X-ray powder diffraction (XRPD) and Fourier-transformed infrared (FTIR) spectroscopy in quantifying mixtures of carbamazepine polymorphs (forms I and III), saccharin, and carbamazepine–saccharin cocrystals (form I) is assessed. Quaternary crystalline mixtures typically produced in the process of co-crystal production were analyzed by multivariate methods. Principal component analysis (PCA) was used for the identification of the crystal phases, while unsupervised simultaneous fitting of the spectra from pure phases, or supervised partial least squares (PLS) methods were used for their quantitative determination. The performance of data analysis was enhanced by applying peculiar pre-processing methods, such as SNIP filtering in case of FTIR and PCA filtering in case of XRPD. It was found that, for XRPD data, the automatic multi-fitting procedures and PLS models developed in this study are able to quantify single phases in mixtures to an accuracy level comparable to that obtained by the widely used Rietveld method, which, however, requires knowledge of the crystal structures. For FTIR data the results here obtained prove that this technique can be used as a fast method for polymorph characterization.

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.

Direct production of carbamazepine–saccharin cocrystals from water/ethanol solvent mixtures by membrane-based crystallization technology

This communication reports on the possibility to achieve the direct production of either carbamazepine crystals or carbamazepine–saccharin cocrystals from water/ethanol solvent mixtures by using membrane-based crystallization technology, by choosing the opportune initial conditions.

Polymorphism in Carbamazepine Cocrystals

Cocrystals of carbamazepine with nicotinamide and saccharin are shown to be polymorphic. Two polymorphs of carbamazepine-nicotinamide (CBZ-NCT) cocrystals and two polymorphs of carbamazepine-saccharin (CBZ-SAC) cocrystals were grown from solution in the presence of polymer heteronuclei. The two CBZ-NCT polymorphs, CBZ-NCT I and a polymer nucleated (PN) form of CBZ-NCT, were characterized by Raman spectroscopy and powder X-ray diffraction. CBZ-SAC II, a new polymorph, was found to be in the monoclinic space group C2/c with a = 35.72 Å, b = 6.84 Å, c = 16.11 Å, and β = 98.03°. The unique feature of CBZ-SAC II is the formation of a heterosynthon between the carbamazepine and saccharin. These results are notable because CBZ-NCT and CBZ-SAC are among the most widely studied pharmaceutical cocrystals.