Carbamazepine-saccharin Cocrystal Research Articles

Impact of the SAC:CBZ ratio on polymorphic transformation and morphology of carbamazepine-saccharin co-crystals using fast cooling crystallization

Impact of the SAC:CBZ ratio on polymorphic transformation and morphology of carbamazepine-saccharin co-crystals using fast cooling crystallization

Mesoscale clusters in multicomponent systems: the effect of solution preparation and pre-treatment on primary nucleation of a carbamazepine-saccharin cocrystal

Nucleation of a cocrystal from solution shows a dependence on pre-treatment conditions, and on whether solutions are prepared by dissolving the cocrystal solids or the two separate coformers.

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.

Exposing Key Vibrational Contributions to Properties of Organic Molecular Solids with High Signal, Low Frequency Neutron Spectroscopy and Ab Initio Simulations

Stability and response of supramolecular forms is important to many areas in materials science, and contributions from vibrations can be crucial. We have collected the first spectra of organic molecular crystals and polymorphic cocrystals using the next-generation, high-signal VISION spectrometer in the far-infrared (FIR) and mid-infrared (MIR) range. Unambiguously different spectral signatures were found for carbamazepine and two polymorphs of the carbamazepine-saccharin cocrystal, including numerous modes undetectable with optical methods. For FIR-range frequencies, in addition to correct calculation of peak positions, accurate line-shape features were reproducible by simulation using ab initio vibrational calculations. High confidence spectral assignments and thermochemical information for this region are thus expected, and a benchmark for vibrational ab initio calculations is provided, creating a significant addition to methods used in investigation and design of organic materials.

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.

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.

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.

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.

Pharmaceutical characterisation and evaluation of cocrystals: Importance of in vitro dissolution conditions and type of coformer

The objectives of this study were to demonstrate the importance of experimental set-up and type of coformer for the enhanced dissolution properties of cocrystals. Carbamazepine-saccharin and carbamazepine-nicotinamide cocrystals were prepared by the sonic slurry method and characterised with SEM, DSC, XRPD and particle size analysis. Solubility and dissolution testing (closed and open system) were performed in compendial media and media with a physiologically relevant amount of surfactant. Carbamazepine cocrystals (1:1 molar ratio) did not show a difference in the equilibrium solubility compared to the carbamazepine in compendial media but a substantial difference was observed in modified media. In compendial media, a faster dissolution rate was obtained only from the carbamazepine-saccharin cocrystal, whereas in modified media both cocrystals had a substantial higher dissolution compared to carbamazepine. With the selected method a clear difference in the dissolution profiles of each cocrystal is shown, driven by the characteristics of the coformer used. This study demonstrated that improved dissolution of carbamazepine from the cocrystal forms can be revealed only by appropriate selection of in vitro conditions. The characteristics of the coformer define a critical variable for dissolution of pharmaceutical cocrystals with important implications for their in vivo performance.

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.

Selecting the Desired Solid Form by Membrane Crystallizers: Crystals or Cocrystals

This work aims to describe a systematic study on the conditions promoting the selective formation of carbamazepine-saccharin cocrystals or single component crystals from water/ethanol solvent mixtures, by using a membrane crystallization process. Results revealed the ability to operate in the proper zone of the phase diagram of the system when opportunely choosing the initial solution conditions and limiting the maximum level of supersaturation by using the membrane-based technology. Control in the selective crystallization of a specific solid form can be achieved by adjusting the solvent evaporation through the micropores of the membrane. Furthermore, the direct correlation between transmembrane flow and polymorphic composition in the case of carbamazepine precipitation confirmed the possibility to produce particular metastable phases upon increasing the supersaturation rate.

Cocrystal Formation during Cogrinding and Storage is Mediated by Amorphous Phase

The purpose of this work was to investigate the mechanisms of cocrystal formation during cogrinding and storage of solid reactants, and to establish the effects of water by cogrinding with hydrated form of reactants and varying RH conditions during storage. The hydrogen bonded 1:1 carbamazepine-saccharin cocrystal (CBZ-SAC) was used as a model compound. Cogrinding of solid reactants was studied under ambient and cryogenic conditions. The anhydrous, CBZ (III), and dihydrate forms of CBZ were studied. Coground samples were stored at room temperature at 0% and 75% RH. Samples were analyzed by XRPD, FTIR and DSC. Cocrystals prepared by cogrinding and during storage were similar to those prepared by solvent methods. The rate of cocrystallization was increased by cogrinding the hydrated form of CBZ and by increasing RH during storage. Cryogenic cogrinding led to higher levels of amorphization than room temperature cogrinding. The amorphous phase exhibited a T (g) around 41 degrees C and transformed to cocrystal during storage. Amorphous phases generated by pharmaceutical processes lead to cocrystal formation under conditions where there is increased molecular mobility and complementarity. Water, a potent plasticizer, enhances the rate of cocrystallization. This has powerful implications to control process induced transformations.