Carbamazepine Cocrystals Research Articles

Using synchrotron high-resolution powder X-ray diffraction for the structure determination of a new cocrystal formed by two active principle ingredients.

The crystal structure of a new 1:1 cocrystal of carbamazepine and S-naproxen (C15H12N2O·C14H14O3) was solved from powder X-ray diffraction (PXRD). The PXRD pattern was measured at the high-resolution beamline CRISTAL at synchrotron SOLEIL (France). The structure was solved using Monte Carlo simulated annealing, then refined with Rietveld refinement. The positions of the H atoms were obtained from density functional theory (DFT) ground-state calculations. The symmetry is orthorhombic with the space group P212121 (No. 19) and the following lattice parameters: a = 33.5486 (9), b = 26.4223 (6), c = 5.3651 (10) Å and V = 4755.83 (19) Å3.

Cocrystals of carbamazepine: Structure, mechanical properties, fluorescence properties, solubility, and dissolution rate

Carbamazepine (CBZ) is an anticonvulsant with very low water solubility, presenting as a white crystalline powder with poor mechanical properties and is hard to bend. To enhance CBZ’s physicochemical properties, such as water solubility and mechanical properties, we selected six cocrystal coformers (CCFs): nicotinamide (NIC), benzamide (BZM), salicylic acid (SCA), fumaric acid (FMA), trimesic acid (TMA), and hesperetin (HPE). Six CBZ cocrystals were successfully prepared using the solution method. Fourier transform infrared spectroscopy (FT-IR), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and single crystal X-ray diffraction (SCXRD) were used to characterize the crystal structures and gain comprehensive insights into the six cocrystals. The mechanical, fluorescence, and solubility properties of the six cocrystals were tested. The results reveal that most of the prepared cocrystals exhibit improved water solubility and mechanical properties when compared to CBZ. Among them, the dissolution rate of cocrystals excluded from CBZ-HPE has increased by an average of 3 or 4 times compared to CBZ, while CBZ-HPE exhibits superior mechanical properties. Moreover, all six cocrystals possess better fluorescence performance than CBZ. We thoroughly evaluated the mechanical properties of the cocrystals through both experimental and theoretical approaches. This work provides a new direction for studying drug cocrystals to improve the physicochemical properties of drugs.

Polymorphism of Carbamazepine Pharmaceutical Cocrystal: Structural Analysis and Solubility Performance.

Polymorphism is a common phenomenon among single- and multicomponent molecular crystals that has a significant impact on the contemporary drug development process. A new polymorphic form of the drug carbamazepine (CBZ) cocrystal with methylparaben (MePRB) in a 1:1 molar ratio as well as the drug's channel-like cocrystal containing highly disordered coformer molecules have been obtained and characterized in this work using various analytical methods, including thermal analysis, Raman spectroscopy, and single-crystal and high-resolution synchrotron powder X-ray diffraction. Structural analysis of the solid forms revealed a close resemblance between novel form II and previously reported form I of the [CBZ + MePRB] (1:1) cocrystal in terms of hydrogen bond networks and overall packing arrangements. The channel-like cocrystal was found to belong to a distinct family of isostructural CBZ cocrystals with coformers of similar size and shape. Form I and form II of the 1:1 cocrystal appeared to be related by a monotropic relationship, with form II being proven to be the thermodynamically more stable phase. The dissolution performance of both polymorphs in aqueous media was significantly enhanced when compared with parent CBZ. However, considering the superior thermodynamic stability and consistent dissolution profile, the discovered form II of the [CBZ + MePRB] (1:1) cocrystal seems a more promising and reliable solid form for further pharmaceutical development.

Virtual Screening, Structural Analysis, and Formation Thermodynamics of Carbamazepine Cocrystals

In this study, the existing set of carbamazepine (CBZ) cocrystals was extended through the successful combination of the drug with the positional isomers of acetamidobenzoic acid. The structural and energetic features of the CBZ cocrystals with 3- and 4-acetamidobenzoic acids were elucidated via single-crystal X-ray diffraction followed by QTAIMC analysis. The ability of three fundamentally different virtual screening methods to predict the correct cocrystallization outcome for CBZ was assessed based on the new experimental results obtained in this study and data available in the literature. It was found that the hydrogen bond propensity model performed the worst in distinguishing positive and negative results of CBZ cocrystallization experiments with 87 coformers, attaining an accuracy value lower than random guessing. The method that utilizes molecular electrostatic potential maps and the machine learning approach named CCGNet exhibited comparable results in terms of prediction metrics, albeit the latter resulted in superior specificity and overall accuracy while requiring no time-consuming DFT computations. In addition, formation thermodynamic parameters for the newly obtained CBZ cocrystals with 3- and 4-acetamidobenzoic acids were evaluated using temperature dependences of the cocrystallization Gibbs energy. The cocrystallization reactions between CBZ and the selected coformers were found to be enthalpy-driven, with entropy terms being statistically different from zero. The observed difference in dissolution behavior of the cocrystals in aqueous media was thought to be caused by variations in their thermodynamic stability.

Formation Thermodynamics of Carbamazepine with Benzamide, Para-Hydroxybenzamide and Isonicotinamide Cocrystals: Experimental and Theoretical Study.

Formation thermodynamic parameters for three cocrystals of carbamazepine (CBZ) with structurally related coformers (benzamide (BZA), para-hydroxybenzamide (4-OH-BZA) and isonicotinamide (INAM)) were determined by experimental (cocrystal solubility and competitive reaction methods) and computational techniques. The experimental solubility values of cocrystal components at eutectic points and solubility product of cocrystals [CBZ + BZA], [CBZ + 4-OH-BZA], and [CBZ + INAM] in acetonitrile at 293.15 K, 298.15 K, 303.15 K, 308.15 K, and 313.15 K were measured. All the thermodynamic functions (Gibbs free energy, enthalpy, and entropy) of cocrystals formation were evaluated from the experimental data. The crystal structure of [CBZ + BZA] (1:1) cocrystal was solved and analyzed by the single crystal X-ray diffractometry. A correlation between the solubility products and pure coformers solubility values has been found for CBZ cocrystals. The relationship between the entropy term and the molecular volume of the cocrystal formation has been revealed. The effectiveness of the estimation of the cocrystal formation thermodynamic parameters, based on the knowledge of the melting temperatures of active pharmaceutical ingredients, coformers, cocrystals, as well as the sublimation Gibbs energies and enthalpies of the individual components, was proven. A new method for the comparative assessment of the cocrystal stability based on the H-bond propensity analysis was proposed. The experimental and theoretical results on the thermodynamic parameters of the cocrystal formation were shown to be in good agreement. According to the thermodynamic stability, the studied cocrystals can be arranged in the following order: [CBZ + 4-OH-BZA] > [CBZ + BZA] > [CBZ + INAM].

SpeedMixing: Rapid Tribochemical Synthesis and Discovery of Pharmaceutical Cocrystals without Milling or Grinding Media.

We present SpeedMixing, a rapid blending technology, as an approach for fast mechanosynthesis and discovery of model pharmaceutical cocrystals through rapid spinning in the absence of bulk solvents and milling/grinding media. Syntheses of pharmaceutical cocrystals based on the active pharmaceutical ingredients (APIs) carbamazepine, dihydrocarbamazepine, and nicotinamide demonstrate SpeedMixing as a method for rapid, scalable, as well as controllable and selective synthesis of cocrystals, cocrystal polymorphs and stoichiomorphs, including the discovery of an unexpected methanol solvate of the archetypal cocrystal of carbamazepine and saccharin, which has eluded extensive screens over 20 years.

SpeedMixing: Rapid Tribochemical Synthesis and Discovery of Pharmaceutical Cocrystals without Milling or Grinding Media**

AbstractWe present SpeedMixing, a rapid blending technology, as an approach for fast mechanosynthesis and discovery of model pharmaceutical cocrystals through rapid spinning in the absence of bulk solvents and milling/grinding media. Syntheses of pharmaceutical cocrystals based on the active pharmaceutical ingredients (APIs) carbamazepine, dihydrocarbamazepine, and nicotinamide demonstrate SpeedMixing as a method for rapid, scalable, as well as controllable and selective synthesis of cocrystals, cocrystal polymorphs and stoichiomorphs, including the discovery of an unexpected methanol solvate of the archetypal cocrystal of carbamazepine and saccharin, which has eluded extensive screens over 20 years.

Low-Frequency Vibrational Spectroscopy Characteristic of Pharmaceutical Carbamazepine Co-Crystals with Nicotinamide and Saccharin.

The pharmaceutical co-crystal has attracted increasing interest due to the improvement of physicochemical properties of active pharmaceutical ingredients. The characterization of pharmaceutical co-crystal is an integral part of the pharmaceutical field. In this paper, the low-frequency vibrational properties for carbamazepine co-crystals with nicotinamide and saccharin (CBZ-NIC and CBZ-SAC) have been characterized by combining the THz spectroscopy with low-wavenumber Raman spectroscopy. The experiment results show that, compared with the individual constituents, CBZ-NIC and CBZ-SAC co-crystals not only have different characteristic absorption peaks in the 0.3-2.5 THz region, but also have significant low-wavenumber Raman characteristic peaks in 0–100 cm−1. Density functional theory was performed to simulate the terahertz and low-wavenumber Raman spectra of the two co-crystals, where the calculation agreed well with the measured vibrational peak positions. The vibrational modes of CBZ-NIC and CBZ-SAC co-crystals were assigned through comparing theoretical results with the experimental spectra. Meanwhile, the low-frequency infrared and/or Raman active of characteristic peaks for such co-crystals were discussed. The results indicate the combination of THz spectroscopy and low-wavenumber Raman spectroscopy can provide more comprehensive low-frequency vibrational information for pharmaceutical co-crystals, such as collective vibration and skeleton vibration, which could play an important role in pharmaceutical science.

Dissolution Profiles of Carbamazepine Cocrystals with Cis-Trans Isomeric Coformers.

The purpose of the present study was to investigate the dissolution profiles of cocrystals with cis-trans isomeric coformers. Previously, the carbamazepine (CBZ) cocrystals with even-carbon dicarboxylic acids showed higher supersaturation than those with odd-carbon ones, attributed to particle surface solution-mediated phase transformation (PS-SMPT) to CBZ dihydrate (CBZ DH). However, it has been unknown whether this odd-even pattern holds for cis-trans isomeric coformers. CBZ cocrystals with maleic acid (MLE) and fumaric acid (FUM) (CBZ-FUM anhydrate (CBZ-FUM AH) and monohydrate (CBZ-FUM H2O)) were employed as model cocrystals. Hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone, and polyethylene glycol 6000 (PEG) were used as precipitation inhibitors. Dissolution tests were performed under a non-sink condition. Residual particles were analyzed by powder X-ray diffraction, differential scanning calorimetry, polarized light microscope, and scanning electron microscope. All cocrystals showed little supersaturation in the absence of a polymer. In 0.1% HPMC, CBZ-FUM AH showed significant supersaturation, whereas CBZ-MLE and CBZ-FUM H2O did not for the first two hours. HPMC reduced the initial dissolution rate of CBZ-MLE and CBZ-FUM H2O while inducing the highest supersaturation among the polymers after 96h. The particle surface changed from a smooth plane to a striped pattern, but little or no CBZ DH was detected. The cocrystals with cis-trans isomeric coformers showed different dissolution profiles. HPMC increased the dissolution rate of CBZ-FUM AH by inhibiting PS-SMPT but reduced the dissolution rate of CBZ-MLE and CBZ-FUM H2O without inducing PS-SMPT. The striped pattern was suggested to be due to surface etching rather than PS-SMPT.

Crystal engineering of valproic acid and carbamazepine to improve hygroscopicity and dissolution profile

Sodium valproate, the most common solid form of valproic acid, is highly hygroscopic and carbamazepine has extremely low aqueous solubility. Producing a salt form of valproic acid with tromethamine and a cocrystal form of valproic acid with carbamazepine have been studied as two approaches to improve physicochemical properties of the intended drugs. Characterization methods including differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FTIR) are applied to characterize the synthesized salt and cocrystal. The stability of sodium valproate and tromethamine valproate were examined in 33, 53, 75 and 100 percent of relative humidity. The dissolution profile studies were performed in phosphate buffer media (pH = 6.8) for carbamazepine (a low soluble drug) and carbamazepine-valprocic acid cocrystal. Tromethamine valproate was physically more stable than sodium valproate in exposure to humidity. Carbamazepine-valproic acid cocrystal did not show an extreme improvement in dissolution profile when compared with carbamazepine, however after 24 hcocrystal was more soluble.

Fabrication of Carbamazepine Cocrystals: Characterization, In Vitro and Comparative In Vivo Evaluation.

Carbamazepine (CBZ) is an antiepileptic drug having low bioavailability due to its hydrophobic nature. In the current study, efforts are made to investigate the effect of dicarboxylic acid coformer spacer groups (aliphatic chain length) on physicochemical properties, relative humidity (RH) stability, and oral bioavailability of CBZ cocrystals. Slurry crystallization technique was employed for the preparation of CBZ cocrystals with the following coformers: adipic (AA), glutaric (GA), succinic (SA), and malonic acid (MA). Powder X-ray diffractometry and Fourier-transform infrared spectroscopy confirmed cocrystal preparation. Physicochemical properties, RH stability, and oral bioavailability of cocrystals were investigated. Among the prepared cocrystals, CBZ-GA showed maximum solubility as well as improved dissolution profile (CBZ-GA > CBZ-MA > CBZ-AA > pure CBZ > CBZ-SA) in ethanol. Maximum RH stability was shown by CBZ-AA, CBZ-SA, and CBZ-MA. In vivo studies confirmed boosted oral bioavailability of cocrystals compared to pure CBZ. Furthermore, in vivo studies depicted the oral bioavailability order of cocrystals as CBZ-GA > CBZ-MA > Tegral® > CBZ-AA > CBZ-SA > pure CBZ. Thus, pharmaceutical scientists can effectively employ cocrystallization technique for tuning physicochemical properties of hydrophobic drugs to achieve the desired oral bioavailability. Overall, results reflect no consistent effect of spacer group on physicochemical properties, RH stability, and oral bioavailability of cocrystals.

Phase solubility investigation and theoretical calculations on drug-drug cocrystals of carbamazepine with Emodin, Paeonol

Carbamazepine (CBZ), a Biopharmaceutics Classification System (BCS) class II drug, is widely-used as a first line antiepileptic drug. Numbers of cocrystals have reported to regulate its poor solubility. However, the solubility behaviors are rarely discussed on theoretical calculations and phase solubility diagrams. In this study, two new drug-drug cocrystals (DDC) of CBZ with emodin (EMO, 1: 1) and paeonol (PAE, 1: 1) as conformers, which offer the advantages of synergetic therapy and patient compliance are reported for the first time. The solubilities in water and in pH = 1.2, 6.8 buffer solutions, demonstrating that the rank order is as follows: CBZ-PAE > CBZ > CBZ-EMO. CBZ-PAE presents the biggest solubility at 0.563 ± 0.003 mmoL/L of in water among all the investigated samples. The solubilities of all the starting materials and cocrystals in six pure organic solvents such as methanol, ethanol, 2-propanol, acetone, acetonitrile, ethyl acetate were investigated to discuss the phase solubility diagrams. The results indicate that experimental solubilities are consistent with the theoretical solubilities on consideration of solubility product (Ksp) and solution binding constant (K11) together. The enthalpy differences between cocrystal and its coformer are calculated through the Perdew-Burke-Ernzerhof (PBE) functional with the projector augmented wave (PAW) pseudopotentials. CBZ-EMO presents the lowest enthalpy (−0.38 kcal/mol) with a highly unfavorable solvation energy (2.42 kcal/mol), resulting in unfavorable in an aqueous environment. Overall, the phase solubility diagrams and theoretical calculations support the solubility regulations on DDCs of CBZ.

Understanding stress-induced disorder and breakage in organic crystals: beyond crystal structure anisotropy.

Crystal engineering has advanced the strategies for design and synthesis of organic solids with the main focus being on customising the properties of the materials. Research in this area has a significant impact on large-scale manufacturing, as industrial processes may lead to the deterioration of such properties due to stress-induced transformations and breakage. In this work, we investigate the mechanical properties of structurally related labile multicomponent solids of carbamazepine (CBZ), namely the dihydrate (CBZ·2H2O), a cocrystal of CBZ with 1,4-benzoquinone (2CBZ·BZQ) and the solvates with formamide and 1,4-dioxane (CBZ·FORM and 2CBZ·DIOX, respectively). The effect of factors that are external (e.g. impact stressing) and/or internal (e.g. phase transformations and thermal motion) to the crystals are evaluated. In comparison to the other CBZ multicomponent crystal forms, CBZ·2H2O crystals tolerate less stress and are more susceptible to breakage. It is shown that this poor resistance to fracture may be a consequence of the packing of CBZ molecules and the orientation of the principal molecular axes in the structure relative to the cleavage plane. It is concluded, however, that the CBZ lattice alone is not accountable for the formation of cracks in the crystals of CBZ·2H2O. The strength and the temperature-dependence of electrostatic interactions, such as hydrogen bonds between CBZ and coformer, appear to influence the levels of stress to which the crystals are subjected that lead to fracture. Our findings show that the appropriate selection of coformer in multicomponent crystal forms, targetting superior mechanical properties, needs to account for the intrinsic stress generated by molecular vibrations and not solely by crystal anisotropy. Structural defects within the crystal lattice, although highly influenced by the crystallisation conditions and which are especially difficult to control in organic solids, may also affect breakage.

Preparation of Carbamazepine-Nicotinamide Cocrystal

The focus of this investigation was to prepare the cocrystal of carbamazepine (CBZ) using nicotinamide as a coformer and to compare its different preparation methods. The cocrystal was prepared by grinding, solvent-Assisted grinding and ultrasound-assisted cocrystallization methods. They were characterized by Fourier transform infrared spectroscopy (FT-IR), powder X-ray diffraction (PXRD), and morphology by electron microscopy. In conclusion, ultrasound can be applied as a process intensification parameter along with cooling or slurry cocrystallization to produce pure cocrystals under conditions that might result in crystal mixtures in conventional processes.

Effects of Coformer and Polymer on Particle Surface Solution-Mediated Phase Transformation of Cocrystals in Aqueous Media.

The purpose of the present study was to investigate the effect of the coformer difference on particle surface solution-mediated phase transformation (PS-SMPT) during cocrystal particle dissolution in aqueous media in the absence and presence of polymers. SMPT can occur either in the bulk phase or at the particle surface because drug molecules can be supersaturated at the dissolving cocrystal surface, as well as in the bulk phase. Previously, bulk phase SMPT has been primarily investigated in formulation development. However, little is known about the effects of coformers and polymers on PS-SMPT of cocrystals. In this study, six carbamazepine (CBZ) cocrystals were used as model cocrystals (malonic acid (MAL), succinic acid (SUC), glutaric acid (GLA), adipic acid (ADP), saccharin (SAC), and nicotinamide (NCT); nonsink dissolution tests were performed with or without a precipitation inhibitor (hydroxypropyl methylcellulose (HPMC)) at pH 6.5. The residual particles were analyzed by powder X-ray diffraction, differential scanning calorimetry, polarized light microscopy (PLM), and scanning electron microscopy. Real-time PLM was used to directly observe rapid PS-SMPT. In the absence of HPMC, supersaturation was not observed in the bulk phase for all cocrystals. All cocrystals rapidly transformed to CBZ dihydrate aggregates via PS-SMPT (mostly within 1 min). In contrast, in the presence of 0.1% HPMC, supersaturation was observed for CBZ-SUC, CBZ-ADP, CBZ-SAC, and CBZ-NCT but not for CBZ-MAL and CBZ-GLA. The cocrystals with lower solubility coformers tended to induce higher supersaturation in the bulk phase. The PS-SMPT of CBZ-SUC, CBZ-ADP, and CBZ-SAC was slowed down by HPMC. By suppressing PS-SMPT, the cocrystals exhibited its supersaturation potential, depending on the properties of each coformer. To take advantage of the supersaturation potential of cocrystals to improve oral drug absorption, it is important to suppress particle surface SMPT in addition to bulk phase SMPT.

Mechanistic Understanding of Competitive Destabilization of Carbamazepine Cocrystals under Solvent Free Conditions

Mechanistic understanding of competitive destabilization of carbamazepine:nicotinamide and carbamazepine:saccharin cocrystals under solvent free conditions has been investigated. The crystal phase transformations were monitored using hot stage microscopy, variable-temperature powder X-ray diffraction, and sublimation experiments. The destabilization of the two cocrystals occurs via two distinct mechanisms: vapor and eutectic phase formations. Vapor pressure measurements and thermodynamic calculations using fusion and sublimation enthalpies were in good agreement with experimental findings. The mechanistic understanding is important to maintain the stability of cocrystals during solvent free green manufacturing.

Terahertz spectroscopic characterizations and DFT calculations of carbamazepine cocrystals with nicotinamide, saccharin and fumaric acid.

Carbamazepine cocrystals with nicotinamide, saccharin and fumaric acid were synthesized and characterized by time-domain terahertz spectroscopy. Lattice vibrations of cocrystals with their individual constituents were investigated by means of the dispersion-corrected density functional theory with and without cell parameter constraints. The simulated THz spectra successfully reproduce the features of all the crystals in their experimental spectra. A better agreement between experimental and theoretical THz spectra is achieved when the cell parameter constraints are applied in geometry optimization. Some intensive modes of neat carbamazepine and cocrystals were discussed in terms of the motions of hydrogen bonds. The effect of lattice vibration on these cocrystallizations was further examined to gain insights into the thermodynamics. It is found that lattice vibration is favorable for all these cocrystal formations.

Structure determination of a new cocrystal of carbamazepine and DL-tartaric acid by synchrotron powder X-ray diffraction.

The crystal structure of a new cocrystal of carbamazepine (systematic name: 5H-dibenzo[b,f]azepine-5-carboxamide, C15H12N2O) and DL-tartaric acid (C4H6O6), obtained by liquid-assisted grinding, was solved by powder X-ray diffraction (PXRD). The high-resolution PXRD pattern of this new phase was recorded at room temperature thanks to synchrotron experiments at the European Synchrotron Radiation Facility (Grenoble, France). The starting structural model was generated by a Monte-Carlo simulated annealing method. The final structure was obtained through Rietveld refinement and an energy minimization simulation was used to estimate the H-atom positions. The stability of the proposed structure as a function of temperature was also assessed from molecular dynamics simulations. The symmetry is monoclinic (space group P21/c) and contains eight molecules per unit cell, namely, four DL-tartaric acid and four carbamazepine molecules.

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.

Quantification of a cocrystal and its dissociated compounds in solid dosage form using transmission Raman spectroscopy

The performance of transmission Raman spectroscopy (TRS) for quantifying a cocrystal and its dissociation in solid dosage form was investigated. Some tablets containing 0%–20% (w/w) of a cocrystal of carbamazepine (CBZ)/succinic acid (SUC), 0%–4% of CBZ, 0%–4% of SUC, and 75%–99% of D-mannitol were prepared. The Raman spectra of these tablets were preprocessed using the standard normal variate (SNV) or multiplicative scatter correction (MSC) as well as the Savitzky Golay second derivative, and then, these were used to generate calibration models using partial least squares (PLS) regression. The performance of the model was superior when the MSC preprocessing spectra of the cocrystal between 200 and 1800 cm−1 were used for calibration. The determination coefficient of the PLS calibration curve for the CBZ/SUC cocrystal between 200 and 1800 cm−1 with MSC was 0.97, root mean square error of cross validation (RMSECV) was 1.16, and root mean square error of prediction (RMSEP) was 1.10. As in the case of the CBZ/SUC cocrystal, the performance of the model was superior when the MSC preprocessing spectra of CBZ and SUC between 200 and 1800 cm−1 were used for calibration. These data suggest that TRS is useful for quantifying a cocrystal and its dissociation compounds in solid dosage forms.