Carbamazepine Polymorphs Research Articles

Pharmacokinetics of carbamazepine polymorphs and dihydrate in rats, related to dogs and humans

Species differences in the oral pharmacokinetics and absolute bioavailability (F ( abs )) of carbamazepine polymorphs (form I and form III) and dihydrate were studied. The pharmacokinetics of each form was investigated in rats following a single oral/intravenous administration of 10 mg/kg and an oral dose of 80 mg/kg, which were compared with the published data obtained from dogs and humans. No significant differences were found in their C (max), T (max), AUC(0-∞) and F ( abs ) among the forms at the low dose. However, significant differences were observed at the high dose. The Fabs of each form was markedly reduced with increasing of doses in species (e.g. F ( abs ) in rats ranged from > 82% to 38.4%-56.0%). At a comparable dose, the C (max), and AUC(0-∞) of rats and humans were about 3-10 times higher than in dogs. The absorption rate of form III in rats exhibited a similar trend to that in humans, and was far higher in dogs. A multi-peak phenomenon in plasma curves was observed in rats and humans, but not in dogs. In conclusion, rats appear to be a better predictor of carbamazepine polymorphs absorbed in humans, and form III may be more suitable as a pharmaceutical crystal.

A strategy for producing predicted polymorphs: catemeric carbamazepine form V

A computationally assisted approach has enabled the first catemeric polymorph of carbamazepine (form V) to be selectively formed by templating the growth of carbamazepine from the vapour phase onto the surface of a crystal of dihydrocarbamazepine form II.

Application of design of experiment (DOE) to polymorph screening and subsequent data analysis

Carbamazepine was used as a well characterised model compound to assess three polymorph screening methodologies. It has been shown that parallel crystallisation followed by in situ analysis by XRPD is an excellent way of generating and analysing new solid forms of a substance in situ. Further methodologies utilising aspects of design of experiment (DOE) show that not only can new forms of a substance be found but also that analysis of the input variables against output response (i.e. polymorphic form) allows one to predict the outcome of a crystallisation experiment. Using these methodologies three of the four known anhydrous forms of carbamazepine were found, as were the known dihydrate, acetone and 1,4-dioxane solvates. For a structured carbamazepine polymorph screen, relationships between input variables and output responses were investigated using the software packages Curvaceous Visual Explorer, INForm and FormRules, showing in the case of carbamazepine, the dielectric constant of the solvent seems to play a large role in determining what polymorphic form is obtained from a crystallisation. It is possible to then predict the polymorphic form from a given set of input conditions. It is also possible to optimise the outcome of an experiment i.e. maximise the chances of obtaining the desired form in a crystallisation experiment.

Solvent Effects on the Crystallization and Preferential Nucleation of Carbamazepine Anhydrous Polymorphs: A Molecular Recognition Perspective

This contribution reports the effects of molecular recognition events and solubility on the crystallization of carbamazepine (CBZ) polymorphs from organic solvents. Solvents were chosen on the basis of their hydrogen-bonding potential. Experiments were conducted to (1) measure solubilities and induction times, (2) monitor solution concentrations and solid phase compositions, and (3) identify intermolecular interactions between solvents and CBZ molecules. Primitive monoclinic, CBZ(M), and trigonal, CBZ(Trg), carbamazepine anhydrous polymorphs readily crystallized from the organic solvents. CBZ(Trg) is the metastable form at 25 °C with a solubility approximately 1.2 times that of CBZ(M). Results show that relative nucleation rates of CBZ polymorphs are dependent on the hydrogen-bonding nature of the solvent and are not dependent on solubility. Solvents that primarily accept hydrogen bonds (donor-to-acceptor ratio (d/a) = 0) preferentially crystallized CBZ(Trg), whereas solvents that accept and donate hydrogen bonds (d/a > 0.5) concomitantly crystallized CBZ(M) and CBZ(Trg). Evaluation of the crystal structures shows that specific interactions between acceptor solvents and the CBZ dimer led to the prevention of the molecular motif necessary for CBZ(M) nucleation. It is concluded that intermolecular interactions and specifically the hydrogen-bonding propensity of solvents with CBZ molecules have profound effects on the molecular self-assembly and selective crystallization of CBZ polymorphs.

Towards the understanding and prediction of material changes during micronisation using atomic force microscopy

In this study we aim to explore the potential links between the mechanical properties, micronisation behaviour and surface energy of carbamazepine polymorphs using atomic force microscopy (AFM) measurements of material properties at the nanoscale. Carbamazepine Forms I, II and III were prepared and confirmed using X-ray powder diffraction (XRPD). AFM measurements of indentation hardness, Young's modulus and surface energy were made on the starting material. In addition, the surface energy was measured immediately after micronisation and after storage for four weeks. Carbamazepine polymorphs could be ranked by Young's modulus and hardness. Surface energy measurements showed an increase after micronisation in all cases, and a varying relaxation after storage for four weeks. Form I showed a smaller particle size distribution, indicating more complete micronisation. A promising correlation was observed between the hardness/Young's modulus ratio and the micronisation behaviour, in terms of particle size reduction and surface energy change. The results show potential for the predictive capacity of such an approach, and help to provide a greater understanding of material behaviour and properties during micronisation.

Analysis of 50 Crystal Structures Containing Carbamazepine Using the Materials Module of Mercury CSD

A set of 50 crystal structures containing the molecule carbamazepine (CBZ) have been analyzed using the Materials module within Mercury CSD 2.0. The similarity relationships between all 50 structures were determined based on the analysis of packing motifs. Packing motifs that define the similarity relationships within three separate groups of structures were found to be exclusive to a particular group. The carboxamide homodimer found in all four of the carbamazepine polymorphs is seen to be disfavored compared to the carboxamide−carboxylic acid heterodimer when a coformer molecule with a carboxylic acid group is present. Etter’s rules are found to be broken in a large percentage of the CBZ structures (24%) compared to the overall CSD statistics (2.5%), apparently due to steric hindrance caused by the dibenzazepine group. A group of 14 similar structures has been identified containing ordered or disordered coformer-filled channels. Thirteen new crystal structures containing CBZ and pharmaceutically relevan...

Visualizing Solvent Mediated Phase Transformation Behavior of Carbamazepine Polymorphs by Principal Component Analysis

The purpose of this research is to gain a greater insight into the hydrate formation processes of different carbamazepine (CBZ) anhydrate forms in aqueous suspension, where principal component analysis (PCA) was applied for data analysis. The capability of PCA to visualize and to reveal simplified structures that often underlie large data sets are explored. Different CBZ polymorphs were dispersed separately in aqueous solution, and then recovered and measured by FT-Raman spectroscopy. PCA was employed for visualizing the dynamics of the phase transformation from each CBZ polymorph to the dihydrate (DH). As a comparison to PCA visualization, the transformation process of each CBZ polymorph was quantified using PLS modeling. The results demonstrated that PCA has advantages in presenting the original data in terms of the differences and similarities, and also directly identify the statistical patterns in the data even when the data set is large. These advantages provided greater insight into the measured Raman spectra as well as the phase transformation process of CBZ polymorphs to the DH in aqueous environment.

Elastic Constants and Related Mechanical Properties of the Monoclinic Polymorph of the Carbamazepine Molecular Crystal

Brillouin scattering has been used to probe the acoustic phonons of the monoclinic (P21/c) polymorph of the drug carbamazepine (CBZ III). By sampling a variety of acoustic phonons, the complete elastic constant tensor has been determined for this CBZ polymorph. The diagonal elastic constants c11, c22, c33, c44, c55 and c66 are 10.89, 11.47, 11.32, 3.68, 0.85 and 2.89 GPa, respectively. The elastic constants of CBZ III are effectively governed by nondirected dispersive type interactions similar to aromatic systems with delocalized pi bonds. The bulk modulus and linear compressibility have been calculated from the compliance matrix. The relative strength of intermolecular interactions in different directions is estimated from the linear compressibility plotted in three crystallographic planes. Cauchy's ratio, calculated from the elastic constants, suggests that many-body forces of dispersive interactions contribute significantly to the lattice anharmonicity of CBZ III.

Solid‐State Transition Mechanism in Carbamazepine Polymorphs by Time‐Resolved Terahertz Spectroscopy

Crystal lattice dynamics: By studying the low-energy intermolecular vibrational modes in the far-infrared region it is possible for the first time to resolve the two-step solid-state conversion mechanism in carbamazepine polymorphic forms III and I directly (see picture).

One-solvent polymorph screen of carbamazepine

To emphasize the fact that solvents can be either critical or immaterial in crystallizing specific polymorphs, a method for obtaining multiple polymorphs of a compound using only one solvent is demonstrated. By varying the crystallization temperature and level of supersaturation, three of the four polymorphs of carbamazepine (CBZ; 5 H-dibenz [ b, f]azepine-5-carboxamide) were crystallized from cumene (isopropyl benzene). Form III, also referred to as the primitive monoclinic form, was produced at temperatures below 60 °C from supersaturated solutions concentrated at less than twice the solubility of that form. When the supersaturation was increased to twice the solubility of form III at temperatures below 60 °C, form II, also referred to as the trigonal form, was produced. Form I, also referred to as the triclinic form, was produced regardless of the level of supersaturation at temperatures above 80 °C. Between 60 °C and 80 °C, mixtures of forms were produced. Competition slurries were employed to establish the transition temperature to be between 79 °C and 82 °C for the enantiotropically related forms III and I. These results indicate that crystallization of CBZ from cumene can either be under thermodynamic control or affected by the kinetics of crystallization of metastable forms. This raises the question about the importance of solvent diversity when looking for polymorphs, suggesting that a rational experimental design can be used to greatly reduce the number of solvents and crystallization conditions. The results of this one-solvent polymorph screen correlate somewhat with a phase–solubility diagram for CBZ.

The influence of various excipients on the conversion kinetics of carbamazepine polymorphs in aqueous suspension

The influence of various excipients on the conversion of carbamazepine polymorphs to the dihydrate in aqueous suspension has been investigated. Ten excipients having functional groups which were potentially able to form hydrogen bonds with carbamazepine (group 1: methylcellulose, hypromellose (hydroxypropyl methylcellulose), hydroxypropylcellulose (HPC), 2-hydroxyethylcellulose (HEC), carmellose sodium (sodium carboxymethylcellulose), cellobiose; group 2: povidone (polyvinylpyrrolidone), povidone-vinyl acetate copolymer (povidone/VA) and N-methyl-2-pyrrolidone; group 3: macrogol (polyethylene glycol) and polyethylene oxide-polypropylene oxide copolymer (PEO/PPO)) were selected. Carbamazepine polymorphic forms III and I were dispersed separately into each aqueous excipient solution (0.1%, w/v) for 30 min at room temperature. The inhibition effect of each excipient was quantified using Raman spectroscopy combined with multivariate analyses. The solubility parameter of each excipient was calculated and used for categorizing excipients. Excipients in groups 1 and 2, which had both low solubility parameters (< 27.0 MPa(1/2)) and strong hydrogen bonding groups, inhibited the conversion completely. With increasing solubility parameter, the inhibition effect decreased for group 1 excipients, especially for carbamazepine form I, which had a higher specific surface area. Also, the excipients of group 3, lacking strong hydrogen bonding groups, showed poor inhibition although they had low solubility parameters (< 21.0 MPa(1/2)). This study indicated the importance of both hydrogen bonding interaction and a suitable hydrophobicity (expressed by the solubility parameter) in the inhibition of the conversion of carbamazepine to the dihydrate.

Solvent inclusion in the structural voids of form II carbamazepine: single-crystal X-ray diffraction, NMR spectroscopy and Hirshfeld surface analysis

Single-crystal X-ray diffraction and solution 1H NMR spectroscopy, in conjunction with Hirshfeld surface analysis, give evidence of solvent inclusion in the trigonal polymorph of carbamazepine, which in the unsolvated form is characterised by the presence of large structural voids.

Effect of alkyl chain parity on the face-selective crystal growth of a drug polymorph

Carboxy terminated alkanethiol self-assembled monolayers promote the face-selective nucleation of the P-monoclinic polymorph of carbamazepine; the type of face nucleated depends on the parity of the alkyl chain.

Systematic investigation of the relationships between 25 crystal structures containing the carbamazepine molecule or a close analogue: a case study of the XPac method

The concept of supramolecular constructs (CrystEngCom 2005, 7, 324) is used to compare 25 related crystal structures. This set is based on the carbamazepine (CBZ) molecule and contains four polymorphic modifications of CBZ, 19 multiple-component crystals and two close analogues of CBZ. Common zero- to three-dimensional structure fragments are identified and discussed. Two fragments of closely packed CBZ molecules, a stack and dimer, are identified as the dominating motifs. These are observed in 24 of the 25 structures. The close 2-D similarity relationship, based on the stack motif, between the triclinic and trigonal modifications CBZ is a particularily intriguing case. In contrast, the other two polymorphs of CBZ contain the dimer motif and they exhibit a 1-D similarity. This study demonstrates that the XPac method is a suitable method for the investigation of large sets of related crystal structures. A graphical method for the visualisation of complex similarity relationships is proposed. The results of this work highlight the great importance that the molecular shape plays in the assembly of molecules in the solid state even in such cases where hydrogen bonds are present.

Structural Studies of the Polymorphs of Carbamazepine, Its Dihydrate, and Two Solvates

Structural Studies of the Polymorphs of Carbamazepine, Its Dihydrate, and Two Solvates

Understanding the Influence of Polymorphism on Phonon Spectra: Lattice Dynamics Calculations and Terahertz Spectroscopy of Carbamazepine

Rigid molecule atomistic lattice dynamics calculations have been performed to predict the phonon spectra of the four polymorphs of carbamazepine, and these calculations predict that there should be differences in the spectra of all four forms. Terahertz spectra have been measured for forms I and III, and there are clearly different features between polymorphs' spectra, that are accentuated at low temperature. While carbamazepine adopts the same hydrogen bonded dimers in all of its known polymorphs, the calculations show that differences in packing arrangements of the dimers lead to changes in the frequency ranges for each type of hydrogen bond vibration, giving a physical explanation to the observed differences between the spectra. Although the agreement between calculated and observed spectra does not allow a definitive characterization of the spectra, it is possible to make tentative assignments of many of the observed features in the terahertz region for the simpler form III; we can only make some tentative assignments of specific modes in the more complex spectrum of form I. While harmonic rigid molecule lattice dynamics shows promise for understanding the differences in spectra between polymorphs of organic molecules, discrepancies between observed and calculated spectra suggest areas of improvement in the computational methods for more accurate modeling of the dynamics in molecular organic crystals.

Characterizing the conversion kinetics of carbamazepine polymorphs to the dihydrate in aqueous suspension using Raman spectroscopy

In an aqueous environment, polymorphic forms I–III of carbamazepine all convert to the dihydrate. This study investigated the conversion of each polymorphic form individually and of a mixture of forms III and I to the dihydrate. Two batches of form I with different crystal morphology were used. Samples were dispersed independently in water at 23 ± 1 °C and recovered at various timepoints varying from 10 to 210 min. Scanning electron microscopy, X-ray powder diffraction and Raman spectroscopy were used to characterize the initial polymorphic forms and the recovered samples after 210 min. Raman spectroscopy combined with partial least squares analysis was used to generate quantitative models of binary and ternary mixtures of the different polymorphic forms with the dihydrate. On the basis of these models the conversion kinetics of the polymorphic forms I–III were characterized. First-order kinetics with an unconverted portion were used to model the data ( R 2 ≥ 0.95). The unconverted portions ranged from 16 to 51% after dispersion for 210 min. The conversion kinetics were similar between polymorphic forms with comparable crystal morphology, but differed significantly between batches of the same polymorph (form I) with different crystal morphology. Furthermore, the conversion of forms III and I in the aqueous suspension was not influenced by the presence of the other polymorph when dispersed together.

Structural Studies of the Polymorphs of Carbamazepine, Its Dihydrate, and Two Solvates

High-field cross-polarisation magic-angle spinning 13C NMR spectra are presented for the four known polymorphs of anhydrous carbamazepine, for a dihydrate, and for two solvates. These are all distinctive, despite relatively low spectral dispersion, and give immediate information about the crystallographic asymmetric unit. The results for the trigonal and the two monoclinic forms are consistent with the published crystal structures. That of the triclinic form was found to contain four molecules in the crystallographic asymmetric unit, which has recently been confirmed by an X-ray diffraction study. NMR shows that the dihydrate has one molecule in the asymmetric unit, and the full crystal structure derived from single-crystal X-ray diffraction work is reported herein. It is found to be ordered and monoclinic, in contrast to the reported disordered orthorhombic structure. The discrepancy is attributed to the common occurrence of multiple micro-twinning. Shielding computations using a method which takes explicit account of the repetition inherent in a crystal lattice are reported for the P-monoclinic form and are compared to the experimental chemical shifts. The NMR data of all the forms are discussed in relation to variations in the molecular geometry of the hydrogen-bonded dimers (except in the case of two solvates). Chemical shift variations are explored as a function of the amide torsion using the Gaussian computer program.

Use of in situ FT-Raman spectroscopy to study the kinetics of the transformation of carbamazepine polymorphs

The solid-state transformation of carbamazepine from form III to form I was examined by Fourier Transform Raman spectroscopy. Using a novel environmental chamber, the isothermal conversion was monitored in situ at 130 °C, 138 °C, 140 °C and 150 °C. The rate of transformation was monitored by taking the relative intensities of peaks arising from two C H bending modes; this approach minimised errors due to thermal artefacts and variations in power intensities or scattering efficiencies from the samples in which crystal habit changed from a characteristic prism morphology (form III) to whiskers (form I). The solid-state transformation at the different temperatures was fitted to various solid-state kinetic models of which four gave good fits, thus indicating the complexity of the process which is known to occur via a solid–gas–solid mechanism. Arrhenius plots from the kinetic models yielded activation energies from 344 kJ mol −1 to 368 kJ mol −1 for the transformation. The study demonstrates the value of a rapid in situ analysis of drug polymorphic type which can be of value for at-line in-process control.

A theoretical and spectroscopic study of carbamazepine polymorphs

AbstractThe drug carbamazepine has been modeled, using ab initio density functional theory calculations [B3LYP/6–31G(d)], both as a single molecule and as a dimer. The predicted geometry of the single molecule calculation is compared with the crystallographic data on each of the polymorphs (carbamazepine forms I and III). From the predicted geometry it is possible to calculate the IR and Raman spectra; these predictions compare favorably with the observed spectra of both polymorphs of carbamazepine for most of the bands. The spectral differences between the polymorphs are more striking in the IR than the Raman spectra, with strong IR bands at 1688 and 1396 cm−1 in form I shifting to 1678 and 1388 cm−1 in form III. Analysis of the potential energy distributions for the calculated normal modes reveals that the vibrations are localized across different ring systems of the carbamazepine structure. Most notably, the polymorph‐sensitive modes in the IR spectra are localized to the pendant CONH2 group; it is these modes that show the greatest disparity from the calculated spectra, and it is this group that is perturbed in the polymorph crystal structures. The calculated dimer structure is similar to that of the single molecule, but the polymorph‐sensitive IR modes are significantly better predicted by the dimer calculation. Copyright © 2004 John Wiley &amp; Sons, Ltd.