Carbamazepine Cocrystals Research Articles

Crystal structure and energetic features of the cocrystal of carbamazepine with 3,5-dinitrobenzoic acid.

The synthesis and detailed description of the crystal structure and energetic features of the 1:1 cocrystal of carbamazepine (5H-dibenzo[b,f]azepine-5-carboxamide, CBZ) with 3,5-dinitrobenzoic acid (35DNBA), i.e. C15H12N2O·C7H4N2O6, are reported. The CBZ and 35DNBA molecules are packed in alternately arranged layers. Two characteristic R22(8) and R22(16) hydrogen-bond ring motifs have been found. The supramolecular architecture, besides the network of hydrogen bonds, is also stabilized by numerous C-H...π, C=O...π, N-O...π, N-O...C and C=O...N weak intermolecular contacts involving neighbouring molecules in the crystal network. Identified interactions have been discussed in detail on the basis of a structural and energetic analysis. The latter approach, performed using the Pixel and CrystalExplorer programs, yielded additional information about the lattice energy and energetic landscape of the respective interactions in the crystal of CBZ·3DNBA with the evaluation of electrostatic, polarization, repulsion and dispersion terms.

Expedited Tablet Formulation Development of a Highly Soluble Carbamazepine Cocrystal Enabled by Precipitation Inhibition in Diffusion Layer.

To address the problem of precipitation of a poorly soluble drug during dissolution of highly soluble cocrystals by preparing granules intimately mixed with a water-soluble polymer. Effectiveness of polymers as precipitation inhibitors during the dissolution of carbamazepine-nicotinamide (CBZ-NCT) cocrystal was assessed based on induction time of crystallization from a supersaturated solution in presence of different polymers at two concentrations. Dissolution was evaluated by both intrinsic dissolution rate (IDR) and USP dissolution method. Powder manufacturability was assessed using a shear cell and compaction simulator to assess flowability and tabletability, respectively. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) was the most effective polymer against precipitation of CBZ and the IDR of a 1:1 (w/w) CBZ-NCT/HPMCAS mixture was the highest. The final formulation of 1:1 CBZ-NCT/HPMCAS granule exhibited excellent flowability, good tabletability, and significantly improved drug release rate than cocrystal formulations without HPMCAS or the CBZ formulation. The particle engineering strategy of modifying the diffusion layer on the surface of highly soluble cocrystal with a polymer is effective for inhibiting premature precipitation of CBZ. Assisted with predictive tools for characterizing powder flowability and tabletability, the design of high quality tablet product with improved drug release rate and manufacturability can be achieved in an efficient manner.

Carbamazepine cocrystals with several aromatic carboxylic acids in different stoichiometries: Structures and solid state characterization

A series of carbamazepine cocrystals with aromatic carboxylic acids have been prepared, including (CBZ)1(DBA)1, (CBZ)2(DBA)1(CH3OH)1 (DBA = 2,3-dihydroxy benzoic acid), (CBZ)1(NA)1(H2O)1 (NA = 1-naphthoic acid) and (CBZ)1(AC)1 (AC = anthracene-9-carboxylic acid). The synthons formed in CBZ cocrystals, e.g. amide···acid heterodimer, amide···amide homodimer, and amide···acid···H2O heterosynthon have been discussed and compared with synthons in reported CBZ cocrystals in CSD. The solid state properties of these cocrystals, such as transformation, solubility and their stabilities have been discussed in the article.

Polymorphism in the co-crystallization of the anticonvulsant drug carbamazepine and saccharin using supercritical CO2 as an anti-solvent

1:1 Co-crystals of carbamazepine (CBZ) and saccharin (SAC) were obtained for the first time through the supercritical anti-solvent (SAS) technique based on using supercritical CO2 as anti-solvent. The capability of SAS to produce the desired polymorphic form (two polymorphs are known) was assessed. Operational conditions investigated were temperature (40.0 and 60.0 °C), pressure (10.0 and 15.0 MPa), solvent choice and coformer concentration in the organic solution (CBZ: 30 and 15 mg/mL; SAC: stoichiometric ratio). Co-crystals were characterized in terms of crystallinity and coformers interactions. No homocrystals were present. Using methanol, at 40.0 °C polymorph I was obtained with yields up to 65%; whilst at 60.0 °C a mixture of polymorphs was obtained. Mixtures of polymorphs were also obtained in the ethanol and dichloromethane experiments at the studied conditions while the dimethylsulfoxide experiments failed to produce any co-crystal polymorph. For comparison purposes, pure CBZ and SAC were also processed by SAS.

Preparation and Characterization of Cabamazepine Cocrystal in Polymer Solution.

In this study, we attempted to prepare carbamazepine (CBZ) cocrystal through the solution method in ethanol-water solvent mixture (volume ratio 1:1) and polyvinyl pyrrolidone (PVP) solution. Nicotinamide (NIC) and saccharin (SAC) were selected as cocrystal coformers. Cocrystal screening products were characterized by Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), and Powder X-ray Diffraction (PXRD) techniques. Characterization results show that in ethanol-water solvent mixture, pure CBZ-NIC cocrystal can be prepared, while CBZ-SAC cocrystal cannot be obtained. The addition of PVP can inhibit CBZ-NIC cocrystal formation and facilitate CBZ-SAC cocrystal formation.

PREPARATION AND EVALUATION OF CO-CRYSTALS OF CARBAMAZEPINE WITH GLUCOMANNAN

Objective: The objective of the present work was to inhibit transformation of carbamazepine anhydrous to its dihydrate form in aqueous medium by adopting the co-crystal approach.Methods: Co-crystallization of carbamazepine and glucomannan as co-former was carried out by solution mediated phase transformation. The solution of carbamazepine and glucomannan in ethanol (95%) was agitated for 2 h and the co-crystals obtained were recovered after 24 h.Results: Co-crystal formation due to hydrogen bonding between carbamazepine and glucomannan as a co-former was confirmed by FTIR study. Inhibition of transformation of co-crystal of carbamazepine to carbamazepine dihydrate in aqueous medium was confirmed by SEM.Conclusion: Inhibition of transformation of carbamazepine co-crystal to its dihydrate form resulted in its improved dissolution. Dissolution efficiency of carbamazepine in its co-crystal was increased up to 79.26% within 30 min.

Electrospray technology as a probe for cocrystal synthesis: Influence of solvent and coformer structure

In the present work electrospray technology has been used for cocrystal synthesis of structurally diverse drug molecules. Additionally, influence of solvent and coformer structure on generation of pharmaceutical cocrystals was also investigated. Carbamazepine (CBZ) and itraconazole (ITZ), structurally diverse molecules with vast difference in physicochemical properties were taken as a model drugs. Nicotinamide (NIC) was used as a coformer for cocrystallization of CBZ. Solutions (methanol and ethanol) of CBZ/NIC (1:1 ratio) were electrosprayed to analyze influence of solvent properties on cocrystal formation. Additionally, cocrystallization of ITZ was attempted using structurally diverse coformers [fumaric acid (FA) and succinic acid (SA)] in 2:1 ratio of drug to coformer. CBZ cocrystals recovered from methanol and ethanol were abbreviated as MCNC and ECNC whereas ITZFA and ITZSA were the abbreviations for cocrystals of ITZ. MCNC and ECNC were recovered in pure form indicating that the solvents screened had no influence on cocrystallization of CBZ. Similarly, ITZSA and ITZFA were recovered in pure form even though the ratio of API to coformer was 2:1 suggesting specificity of the electrospray technology. Thus electrospray technology, a single step, selective method for continuous manufacturing of cocrystals can serve as an alternative to traditional methods of cocrystal synthesis.

Novel drug–drug cocrystals of carbamazepine with para-aminosalicylic acid: screening, crystal structures and comparative study of carbamazepine cocrystal formation thermodynamics

The cocrystal formation of the anticonvulsant drug carbamazepine (CBZ) withpara-aminosalicylic acid (PASA, antituberculous drug) has been studied by varying methods.

Self-templating accelerates precipitation of carbamazepine dihydrate during the dissolution of a soluble carbamazepine cocrystal

Similarly organized carbamazepine (CBZ) clusters in a soluble cocrystal with glutaric acid templated the nucleation and precipitation of poorly soluble CBZ dihydrate during dissolution.

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.

In situ monitoring of vapour-induced assembly of pharmaceutical cocrystals using a benchtop powder X-ray diffractometer.

We describe a simple setup for in situ continuous monitoring of vapour-induced transformations of organic solids using a benchtop powder X-ray diffractometer. Proof-of-principle application of this setup to model pharmaceutical cocrystals reveals complex reactivity, transformations of reaction intermediates within minutes, and a simple route to the rarely observed monoclinic form of the pharmaceutical cocrystal of carbamazepine and saccharin.

Initial dissolution kinetics of cocrystal of carbamazepine with nicotinamide.

Objectives of this study are investigating the initial dissolution kinetics of the cocrystal of carbamazepine (CBZ) with nicotinamide (NIC) and understanding its initial dissolution process. Cocrystal solids of CBZ with NIC were prepared by co-milling and solvent evaporation methods. The formation of cocrystal solid was verified via X-ray diffraction measurement. Dissolution tests of the solids were performed using an original flow cell and ultraviolet-visible spectroscopic detector. The spectra monitored in situ were analyzed to determine the dissolved compounds separately using the classical least squares regression method. The initial dissolution profiles were interpreted using simultaneous model of dissolution and phase changes. In the initial dissolution, CBZ in the cocrystal structure dissolved in water and it was suggested that CBZ reached a metastable intermediate state simultaneously with dissolution. The cocrystal solid prepared by solvent evaporation provided a higher rate constant of the phase change than that prepared by co-milling. Our results thus support the use of evaporation as the method of choice to produce ordered cocrystal structures. We suggest that CBZ forms dihydrate during the dissolution process; however, during the initial phase of dissolution, CBZ changes to a metastable intermediate phase.

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.

HPLC determination of olanzapine and carbamazepine in their nicotinamide cocrystals and investigation of the dissolution profiles of cocrystal tablet formulations

Cocrystals have recently gained importance in the pharmaceutical industry. In this study, olanzapine and carbamazepine cocrystals were synthesized by using nicotinamide as cocrystal forming agent to achieve improvements in the physicochemical characteristics of the active ingredients. An HPLC method was developed to determine the amount, thus, the stoichiometric ratios of olanzapine and carbamazepine in the synthesized cocrystals. Olanzapine:nicotinamide and olanzapine tablet formulations were prepared and the developed HPLC method was applied successfully in order to compare the dissolution profiles of these formulations. An ACE 5 CN, 25 cm × 4.6 mm, 5 µm column was used and a gradient elution program was performed for simultaneous determination of olanzapine, carbamazepine and nicotinamide. Phosphate buffer (pH 5.0, 25 mM) and methanol was used in a ratio from 80:20 to 70:30 while the flow rate was 1 mL min−1 for the elution of the compounds within 12 min. In conclusion, two different aims were achieved, the first one was to indicate the stoichiometric ratios of the active ingredients olanzapine and carbamazepine with nicotinamide in their cocrystals, and the second one was the comparison of the dissolution profiles of the olanzapine and olanzapine:nicotinamide cocrystal formulations. It was found that the cocrystal formulation with nicotinamide improved the dissolution profile of olanzapine.

Production method of carbamazepine/saccharin cocrystal particles by using two solution mixing based on the ternary phase diagram

In the pharmaceutical field, improvement of drug solubility is required, and an interest in cocrystals is growing. Crystallization methods for industrial production of cocrystals have not been developed enough whereas many cocrystals have been prepared in order to find a new crystal form by screening in the laboratory. The objective of this study was the development of the crystallization method which is useful for the industrial production of cocrystal particles based on the phase diagram. A cocrystal of carbamazepine and saccharin was selected as a model substance. The ternary phase diagram of carbamazepine and saccharin in methanol at 303K was measured. A cocrystallization method of mixing two kinds of different eutectic solutions was designed based on the ternary phase diagram. In order to adjust the cocrystallization conditions, the determination method of the driving force for cocrystal deposition such as supersaturation based on mass balance was proposed. The cocrystal particles were obtained under all the conditions of the five mixing ratios. From these experimental results, the relationship between the supersaturation and the induction time for nucleation was confirmed as well as conventional crystallization. In conclusion, the crystallization method for industrial production of cocrystal particles including the determination of the supersaturation was suggested.

Solubility and dissolution rate of a carbamazepine–cinnamic acid cocrystal

Synthesis of cocrystals is one of the methods to alter physicochemical properties of drugs. A cocrystal of carbamazepine (CBZ) and cinnamic acid (CIN) was synthesized using solvent evaporation and was characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR). The kinetic solubility, powder dissolution rate and stability of CBZ in aqueous solution were compared with those of cocrystal form (CBZ–CIN). Quantification of CBZ was evaluated using a UV-spectrophotometric technique in the presence of CIN that their spectrums are highly overlapped. Therefore, a recently developed net analyte signal standard addition method (NASSAM) was applied for determination of CBZ in the presence of CIN. The PXRD, DSC and FT-IR studies confirm that the cocrystal formation between CBZ and CIN and the developed NASSAM method can be used to quantitative determination of CBZ concentration in presence of CIN. The powder dissolution rate of cocrystal of CBZ–CIN is higher than CBZ and the kinetic solubility study show that the cocrystal is stable in dissolution medium and the aqueous solubility of CBZ–CIN is higher than CBZ. These findings show that formation of CBZ–CIN cocrystal is a suitable method to increase dissolution rate and solubility of CBZ and NASSAM is a valuable analytical method to quantitative determination of drugs in the presence of coformer in cocrystal studies.

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.

In vivo brain microdialysis as a formulation-screening tool for a poorly soluble centrally acting drug

Objective: Efficacy of a formulation of a poorly soluble centrally acting drug was evaluated by measuring dopamine responses using in vivo brain microdialysis.Methods: Co-crystals (1:1) of carbamazepine and nicotinamide (CBZ–NCT) were complexed with cyclodextrins (γ-CDs) using supercritical fluid processing. Phase solubility and intrinsic dissolution were studied. Pharmacodynamic studies were performed on rats divided into three groups getting either CBZ–NCT in CD (20 mg/kg CBZ), pure CBZ solution or vehicle. A guide cannula was implanted to attach the microdialysis probe. Dialysate samples were analyzed for dopamine levels, which were compared between groups.Results: The optimized CBZ formulation (5% w/w in γ-CD) with solubility – 10 mg/mL showed stepwise increase in dopamine response (maximum 250% of baseline) compared to neat CBZ or vehicle (p < 0.05). The pharmacokinetics of the drug required 30 min to elicit CNS response, which peaked at about 1.5–2 h.Conclusion: Hence, brain microdialysis was successfully used to evaluate a dissolution rate enhancing formulation.

A comparative assessment of the influence of different crystallization screening methodologies on the solid forms of carbamazepine co-crystals

A comparative examination of different co-crystal screening approaches that employ different crystallization techniques and conditions is presented through the study of a set of sixteen co-crystal forms of carbamazepine (CBZ). The selection of co-crystals used herein captures representation from all the three common packing motifs for CBZ co-crystals. The screening was conducted using non-stoichiometric (addition of CBZ to saturated solutions of co-crystal former (CCF)) and stoichiometric crystallisation (equivalent mol amount of CBZ and CCF) methods. For non-stoichiometric experiments, various mixing regimes were studied, whereas for stoichiometric experiments, evaporation, solvent drop grinding and dry grinding techniques were assessed. An overall success rate of 85% was achieved with the various experiments using the non-stoichiometric approach with respect to co-crystallization, whereas only 61% of the experiments using the stoichiometric approach via grinding (dry and wet) and evaporation produced co-crystals. The findings of this work suggest that, contrary to the common practice wherein grinding and solvent evaporation based methods are most commonly used, the non-stoichiometric crystallization screening method should be first pass screen of choice. This reflects its higher success rate and higher utility towards the overall solid form development process. The fact that in our study, CBZ-GA co-crystals could only be obtained from grinding based methods, nonetheless, clearly illustrates the utility of other screening methods when hits are not obtained from the non-stoichiometric crystallization screening method.

In situ monitoring of carbamazepine–nicotinamide cocrystal intrinsic dissolution behaviour

Cocrystals have shown huge potential to improve the dissolution rate and absorption of a poorly water soluble drug. However, solution mediated phase transformation of cocrystals could greatly reduce the enhancement of its apparent solubility and dissolution rate. The aim of this study is to gain a deep understanding of the phase transition behaviour of cocrystals during dissolution and to investigate the improvement of dissolution rate. Dissolution and transformation behaviour of carbamazepine–nicotinamide (CBZ–NIC) cocrystal, physical mixture and different forms of carbamazepine: form I (CBZ I), form III (CBZ III) and dihydrate (CBZ DH) were studied by different in situ techniques of UV imaging and Raman spectroscopy. It has been found that compared with CBZ III and I, the rate of intrinsic dissolution rate (IDR) of CBZ–NIC cocrystal decreases slowly during dissolution, indicating the rate of crystallisation of CBZ DH from the solution is slow. In situ solid-state characterisation has shown the evolution of conversion of CBZ–NIC cocrystal and polymorphs to its dihydrate form. The study has shown that in situ UV imaging and Raman spectroscopy with a complementary technique of SEM can provide an in depth understanding during dissolution of cocrystals.