In-Line Monitoring of Carvedilol Crystallization Using Raman

Article pubs.acs.org/crystal

In-Line Monitoring of Carvedilol Crystallization Using Raman Spectroscopy Hajnalka Pataki,*,† Imre Markovits,‡ Balázs Vajna,† Zsombor K. Nagy,† and György Marosi† †

Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1111 Budapest, Hungary API Pilot Plant, EGIS Pharmaceuticals PLC, H-1106 Budapest, Hungary

‡

ABSTRACT: Real-time Raman spectroscopy was used to characterize the solvent-mediated polymorphic transition and cooling crystallization of carvedilol. Kinetically preferred Form II was transformed into thermodynamically stable Form I during solvent-mediated phase transitions in ethyl acetate. The transition rate into Form I increased with rising temperature; however, at 0 °C a solvate form (Form VII) appeared. In the case of cooling crystallizations, the Form II polymorph was formed at 16−9 wt % drug concentration, while metastable solvates crystallized from a diluted, 2.9 wt % solution. A new solvate form, Form V*, was identified during crystallization in ethyl acetate, which is presumably related to Form V (known as an ethyl methyl ketone solvate in the literature). This study demonstrates the advantages of in-line Raman spectroscopy for monitoring in situ pharmaceutical crystallization by detecting the intermediate polymorphic transitions, which is fundamental in the development and operation of industrial crystallization processes. emission spectroscopy (AES)16 have also been adapted to qualitatively or quantitatively determine crystal properties (such as crystal size distribution, crystal habit, and morphology) during crystallization. Raman spectroscopy is particularly effective in monitoring crystallization processes, since it provides fast, nondestructive examination and is remarkably suitable for distinguishing polymorphs due to the sharp and selective vibrational bands.17 Both thermodynamic and kinetic aspects of crystallization processes can be evaluated with realtime Raman spectroscopy. Furthermore, the effects of the experimental conditions (solvent or antisolvent selection, temperature profile, cooling and shear rates, characteristics of seed crystals, pH, etc.) on the quality of the final product can be estimated.18−21 The introduction of the process analytical technology (PAT) initiative is expected to be an effective aid to the crystallization procedures. On the basis of a recent FDA directive, this novel mode of operation will transform the manufacturing aspect of the pharmaceutical industry.22,23 The main disadvantages of most current drug production technologies (such as frequent process correction due to returning manufacturing difficulties and accidental production of entire inadequate batches, the need for extensive analytical control of the final products, and time-consuming validation processes) can be reduced or eliminated with the application of technologies with continuous in-/online control. Important steps to put PAT into practice are to apply real-time analytical methods24 and process control algorithms.25,26 Raman spectroscopy is a particularly promising tool for implementing the PAT concept.

1. INTRODUCTION Carvedilol is a nonselective β blocker, used in the treatment of mild to moderate congestive heart failure. It has five different known polymorphs and three solvates. Identifying all possible polymorphs of an active pharmaceutical ingredient is essential, because morphological changes of the drug are accompanied by changes in physical−chemical stability, solubility, and bioavalibility.1 As different crystal structures of a drug are considered as separate pharmaceutical ingredients in a patenting process, it is important to reveal and understand if the formation or transformation of certain polymorphs is possible during manufacturing and/or storage.2−4 An obvious disadvantage of commonly used off-line analytical methods to identify polymorphs (such as X-ray powder diffraction (XRPD), Fourier transformation infrared spectroscopy (FT-IR), solid-state nuclear magnetic resonance (ss-NMR), differential scanning calorimetry (DSC), or thermogravimetry (TG)) is the need for sample preparation, which can alter the original crystal structure of the product. Even before preparation, simply taking samples from the manufacturing (or storage) environment can influence the crystallization process. Furthermore, it cannot always be assured that the samples taken are representative of the whole suspension. All these problems can be avoided by real-time analysis of the crystallization medium during the manufacturing process. Various methods have been developed in recent years for real-time monitoring of crystallization. Solid and liquid phases can be characterized with Fourier transformation infrared spectroscopy (FT-IR),5,6 near-infrared spectroscopy (NIR),7,8 and Raman spectroscopy.9−11 Focused beam reflectance measurement (FBRM),12,13 particle vision measurement (PVM),14 ultrasonic spectroscopy (US),15 and acoustic © 2012 American Chemical Society

Received: August 8, 2012 Published: September 11, 2012 5621

dx.doi.org/10.1021/cg301135z | Cryst. Growth Des. 2012, 12, 5621−5628

Crystal Growth & Design

Article

correction with manually selected baseline points. The spectra were then normalized to unit area in order to eliminate the intensity deviation between the measured spectra caused by the changing crystallization medium. The concentrations of the polymorphic forms in the crystallization medium were calculated using the CLS (classical least squares) method, which relies on a bilinear model and thus is based on the assumption that mixture spectra are linear combinations of the spectra of the pure components,27 according to eq 1.

The aim of this work is to apply the powerful in-line Raman technique during crystallization and the solvent mediated phase transition of carvedilol, and to determine the thermodynamic relationship of its polymorphs in ethyl acetate.

2. MATERIALS AND METHODS 2.1. Materials. Carvedilol ((±)-[3-(9H-carbazol-4-yloxy)-2hydroxypropyl][2-(2-methoxypheoxy)ethyl] amine; Scheme 1), ob-

X = CST + E

Scheme 1. Molecular Structure of Carvedilol

(1)

where S (k × λ) is the set of reference (pure component) spectra, with each spectrum consisting of λ intensity values and forming a row in the ST matrix. X (p × λ) is the matrix containing the in-line Raman spectra accumulated during the crystallization process, and C (p × k) contains the spectral concentrations (each row in C contains the concentrations of the k ingredients). The residual noise is expressed by the matrix E. The spectral concentrations (ratio of the components) can be estimated by eq 2: T

tained from Egis Pharmaceuticals PLC, has five polymorphs (Forms I, II, IV, VII, IX) and three solvates (Forms V, VI, III). The applied solvent was ethyl acetate (water content Form II (80% Form I)

ratio of carvedilol Raman bands became very low at the concentration of 2.9 wt %, external validation was required besides the in-line Raman results. Therefore, real-time Raman monitoring was accompanied by sampling and at-line analysis. In-line Raman spectra were compared to the results of XRPD, 1H NMR, and at-line Raman measurements. The in-line

Form II ≫ Form I (10% Form I) Form II ≫ Form I

1

spectra suggest a complex set of transformations (Figure 10a), where crystallization starts at 2 h (between 5 and 2 °C); then the Raman spectra indicate further transformations at 6 h and at 15 h. (Proper identification of the polymorphic forms at these stages could not be performed due to the low Raman intensites.) The supplementary results based on the vacuum5626



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effective tool to characterize the transition in suspension. Inline Raman spectroscopy provides essential information about different polymorphic alterations of drugs during the crystallization processes, which is fundamental in both product development and the operation of industrial crystallization processes.

dried at-line samples are provided in Figure 10b. At-line Raman spectra, in good agreement with the 1H NMR results (high solvent content ≈40 n/n%), confirm the presence of the new solvate Form V*. (Samples were homogeneous, which was ensured by the uniformity of Raman spectra collected from different areas on the sample.) Figure 10b proves that the unknown intermediates detected by the in-line Raman spectra are stabilized in Form V* solvate after filtration and drying in vacuum at 25 °C. If this product is dried at 70 °C in vacuum, it will recrystallize (through melting) to a mixture of Form I and Form II (according to XRPD). The Raman spectrum and XRPD of the new solvate showed that there was an ethyl acetate molar ratio of 45 n/n%, as shown in Figures 11 and 12. Its crystal structure seems identical with that of Form V solvate on the basis of patent literature, which described Form V as an ethyl methyl ketone solvate.30 The original Form V solvate and this new solvate (where the same crystal structure was prepared in EtOAc) seem to be channel solvates; they just differ in their solvent content. Table 1 shows the transformation of Form V* into other polymorphs under different drying conditions.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank EGIS Pharmaceutical PLC for providing the materials and the equipment, and for their permission to publish this work. The research was supported by the OTKA Research Fund (code K76346). Besides this project is supported by the New Széchenyi Plan (Project ID: TÁ MOP4.2.1/B-09/1/KMR-2010-0002).

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4. CONCLUSIONS Cooling crystallization and solvent-mediated transformation of carvedilol were performed, where Raman spectroscopy was used for the in situ analysis of the polymorphic content in the suspension. Raman spectra of Forms I and II showed distinct differences that could be used to identify crystals in the suspension as well. The main Raman peaks of the dissolved carvedilol were only detectable at 77 °C in the saturated solution (where the drug concentration level was high enough), due to the relatively low Raman activity of the drug. Transformation of the kinetically preferred Form II polymorph into thermodynamically stable Form I was observed entirely at 60 °C and 50 °C and partially at 25 °C after seeding with a small quantity of Form I crystals. The time of transformation increased as a function of process temperature. In contrast, solvates (an undefined solvate and Form VI) appeared during seeded crystallizations at 0 and 25 °C temperatures, respectively. Form II transformed into an undefined solvate via the Form VII intermediate polymorph during the slurry transition at 0 °C. The process was accompanied by a significant decrease in the overall intensity of the in-line Raman spectra. Turbidity and light scattering issues besides the low Raman activity of the appearing solvates could probably be the cause of this phenomenon. Cooling crystallization experiments were carried out at three concentration levels (16 wt %, 9 wt %, 2.9 wt %) by applying a predefined temperature profile. The moments of both the precipitation and dissolution were always clearly identifiable. Formation of the metastable Form II polymorph took place from the concentrated system (16−9 wt %) at all times. In contrast, a new solvate (Form V*) appeared during the cooling crystallization of the diluted (2.9 wt %) solution. The prepared Form V* solvate is unstable, transforming into a mixture of Forms I and II. Form V* solvate is presumably related to Form V, known as an ethyl methyl ketone solvate in the literature. These results show the potential of Raman spectroscopy for process optimization and control; besides, it is a promising technique to understand the relationships between the process parameters and the final crystal morphology. We established that if there are significant differences among the Raman peaks of the different polymorphs, the CLS method can be an

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In-Line Monitoring of Carvedilol Crystallization Using Raman

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