Application of 13C CPMAS NMR for Qualitative and Quantitative Characterization of Carvedilol and its Commercial Formulations

Application of 13C CPMAS NMR for Qualitative and Quantitative Characterization of Carvedilol and its Commercial Formulations 1,2 ´ MONIKA ZIELINSKA-PISKLAK, DARIUSZ MACIEJ PISKLAK,1 IWONA WAWER1 1

Department of Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Warsaw 02-097, Poland

2

Department of Inorganic and Analytical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Warsaw 02-097, Poland

Received 6 July 2011; revised 10 December 2011; accepted 4 January 2012 Published online 13 February 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23062 ABSTRACT: 13 C cross-polarization magic-angle spinning nuclear magnetic resonance (CPMAS NMR) spectroscopy was applied to the identification and characterization of carvedilol (1-(9H-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)-ethylamino]-propan-2-ol) in pharmaceutical preparations. Solid-state spectra (standard linewidth and lack of signal multiplicity) of carvedilol indicate that its physical form is the same (freebase form II); no other polymorphic forms were detected. The spectra of excipients, recorded under the same conditions, were helpful in their identification. The differences in chemical shifts for tablets I–VI are insignificant and suggest that there are no strong intermolecular drug–excipient interactions. The drugs from six manufacturers contained the same amount (25 mg) of the active substance per tablet; however, tablets differ in size and thus in the concentration of carvedilol. An attempt at quantitation of carvedilol in the dosage forms was made. The cross-polarization kinetics and other measurement parameters affecting the intensity and reproducibility of the spectra were determined. The results revealed a satisfying relationship between the composition of the tablets and the intensity of selected NMR signals. The 13 C CPMAS NMR technique was found to provide accurate quantification of drugs without any chemical preparation, as shown by the particular case of carvedilol’s solid formulations. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:1763–1772, 2012 Keywords: solid-state NMR; tablet; formulation; excipients; solid dosage form

INTRODUCTION The solid-state (SS) form (i.e., crystalline, polymorphs, solvates, and amorphous solids) of a drug substance can have a significant impact on the drug’s solubility, dissolution rate, stability, and bioavailability of a pharmaceutical formulation.1–4 The overall characterization and quantitation of pharmaceutical polymorphs and related forms (solvates) in the solid phase can be accomplished by cross-polarization (CP) magic-angle spinning (MAS) nuclear magnetic resonance (CPMAS NMR) spectroscopy. Numerous application studies on pharmaceutical solids using SSNMR have been reported5–13 and reviewed.12,13 Technically, it is relatively easy to handle a powdered sample of a drug and subject it to SSNMR measurement. The assignment of resonances, ´ Correspondence to: Monika Zielinska-Pisklak (Telephone: +48-22-5720-950; Fax: +48-22-5720-950; E-mail: monika. [email protected]) Journal of Pharmaceutical Sciences, Vol. 101, 1763–1772 (2012) © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association

especially for polymorphs, is a more difficult task. However, the most valuable data are obtained by combining SSNMR, X-ray diffraction crystal structure analysis, and theoretical calculations of NMR shielding constants.7–11 Solid-state NMR can be used to distinguish different formulated drug products. An obvious advantage is that the spectra of tablets can be recorded without isolation of the active substance; only the tablet should be powdered. The resonances of the drug and those of excipients can overlap, and crowded spectra of solid formulations are difficult to analyze. If the active substance contains one or more fluorine atoms, 19 F NMR can be employed to analyze the state of the active pharmaceutical ingredient (API) without any interference of excipients. Although there are other techniques suppressing the signals of excipients,14 in some cases, there is a need to characterize all components of the tablet mass. Carvedilol (1-(9H-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)-ethylamino]-propan-2-ol) (Fig. 1) belongs to $-adrenolytics, a large group of cardiovascular

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Figure 1. Molecular structure of carvedilol and the structures of excipients: (a) crospovidone, (b) lactose, (c) saccharose, (d) cellulose, and (e) sodium lauryl sulfate with carbon numbering.

drugs used clinically in the treatment of heart failure, hypertension, and certain types of cardiac arrhythmias. Although $-adrenolytics have similar structural characteristics and similar chemical properties, they differ in their pharmacological properties such as $1 -selectivity, intrinsic sympathomimetic activity, and membrane stabilizing.15 The single-crystal X-ray structure of the (R)-enantiomer of carvedilol phosphate was solved16 in 2010, and used as a starting point to study the disordered racemic crystal structure. A combination of single-crystal X-ray diffraction, SSNMR, and other analytical techniques showed the racemate and (R)-enantiomer to be the hemihydrates. The structure of carvedilol freebase (I) was determined17 in 2007 and showed several significant differences from the already known18 polymorph (II). Although both structures are monoclinic and crystallize in the same space group, the cell parameters and molecular conformations of (I) and (II) are different. A closer look reveals that only two torsion angles are responsible for this difference.

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Several pharmaceutical companies produce preparations containing carvedilol, and a fast method of identification of the active substance in the formulation is required. Furthermore, it is of interest to determine the SS conformation of this drug in pharmaceutical dosage forms using the information from SSNMR spectra. The aim of this study was to characterize the SS form of carvedilol as well as the excipients in carvedilol containing drugs by 13 C CPMAS NMR. Additionally, the potential of SSNMR was used to gain quantitative or near-quantitative results for pharmaceutical solids with carvedilol.

EXPERIMENTAL Materials Carvedilol freebase form II racemate and the excipients (microcrystalline cellulose, sodium lauryl sulphate, crospovidone, lactose, and saccharose) were

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Figure 2. (a) The aromatic region of 13 C CPMAS NMR spectrum of solid carvedilol form II, standard and recorded with dipolar dephase pulse sequence (with 50 :s delay time inserted before acquisition; lower trace). (b) 13 C CPMAS NMR spectrum of pure solid carvedilol form II.

obtained from Pharmaceutical Institute, Warsaw, Poland. The drug formulations, tablets containing 25 mg of carvedilol, were collected from different manufacturers: Dilatrend 25 (Roche, Basel, Switzerland) (I), Carvedilol TEVA 25 (Teva Pharmaceuticals Polska, Warsaw, Poland) (II), Coryol 25 (Krka, Novo Mesto, Slovenia) (III), Carvedilol-ratiopharm 25 (Ratiopharm, Ulm, Germany) (IV), Carvedigamma

25 (W¨orwag Pharma, B¨oblingen, Germany) (V), and Vivacor 25 (Anpharm, Warsaw, Poland) (VI). Methods The 1 H and 13 C NMR spectra of carvedilol were recorded for DMSO-d6 solution on a Bruker DSX400 spectrometer (Bruker BioSpin, Rheinstetten,

Table 1. 13 C NMR Chemical Shifts (δ, ppm) of Carvedilol Form II in DMSO- d6 Solution and Solid State, the Differences  δ = δsolution − δsolid state > 1.0 ppm and the CP Parameters (ms)

C1

C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12

δsolution

δCPMAS

103.82 126.48 100.42 155.98 111.59 121.76 122.49 118.57 124.51 110.33 138.91 141.11

103.4 129.5 100.4 154.3 112.1 122.1 123.1 119.6 126.1 110.4 139.7 139.7

a Overlapped b Overlapped

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TH 1ρ

Tcp

−1.6

156 100 109 418 400 400 174 190 124

0.64 0.35 0.52 1.14 2.22 1.22 0.45 0.3 0.39

a

a

1.4

410b 410b

1.04b 1.04b

* −3.0 −1.7

OC1 OC2 NC3 C1 C2 C3 C4 C5 C6 C7 C8 C9

δsolution

δCPMAS

*

TH 1ρ

Tcp

70.47 68.43 52.61 48.53 68.50 148.10 149.19 112.22 121.02 120.71 113.65 55.43

72.5 69.2 51.5 48.9 70.7 148.1 149.6 110.4 121.4 118.5 110.4 53.5

−2.0

100 115 116 205 104 420 417

0.19 0.24 0.20 0.28 0.28 1.32 1.45

1.1 −2.2

1.8 2.2 3.2 1.9

a

a

155.0 130.9

0.46 0.46

a

a

320

0.43

signal of three carbon atoms. signal of two carbon atoms.

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Figure 3. 13 C CPMAS NMR spectra of (a) carvedilol tablet III—Coryol 25 (Krka), (b) carvedilol form II and pure excipients: (c) crospovidone, (d) saccharose, and (e) lactose. Signals of the excipients in tablet spectrum are marked with color letters: red K—crospovidone, green L—lactose, and dark blue S—saccharose.

Germany) operating at 400.61 (1 H) and 100.13 (13 C) MHz. CPMAS SS 13 C NMR spectra were recorded on a Bruker DSX-400 spectrometer at 100.13 MHz at 298 K. Powdered samples were spun at 10 kHz in 4 mm ZrO2 rotors using double air-bearing probehead (Bruker PH MAS VTN 400WB BL4). Acquisition was performed with a standard CP pulse sequence with JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 5, MAY 2012

two-pulse phase modulation decoupling scheme, using 3.2 :s proton 90◦ pulse and the optimized recycle delay of 10 s. The decoupling field strength was set to 78 kHz. Glycine was used for the Hartmann–Hahn matching procedure and as an external standard; 13 C chemical shifts were referenced to glycine CO at 176.03 ppm with respect to tetramethylsilane (TMS). DOI 10.1002/jps

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Figure 4. 13 C CPMAS NMR spectra of carvedilol tablets: I–Dilatrend 25 (Roche), II—Carvedilol TEVA 25 (Teva Pharmaceuticals), and III—Coryol 25 (Krka). (Signals of the excipients are marked with color letters: red K—crospovidone, green L—lactose, and dark blue S—saccharose.)

Dipolar dephasing (DD) pulse sequence19 (with 10, 25, 50, 75, and 100 :s delay time inserted before acquisition) was used to observe selectively the nonprotonated carbon atoms and rotating methyl groups. All spectra were recorded with 1000 scans, 0.023 s acquisition time, and spectral width of 44 kHz. The 4 k number of Free Induction Decay (FID) points was transformed into 16 k frequency points with line broadening of 10 Hz. The detailed spectrometer settings and data processing followed the protocol for quantitation.13 The variable contact time experiments were performed using contact times varying from 0.025 up to 20 ms. The CP kinetic functions were fitted to the classical (I–S) model. All tablets were weighed on high-resolution analytical balance. The concentration of the API in tablets’ masses was determined by dividing the API content (25 mg in every tablet) by the total tablet weight. Following results were obtained: I—29.99%, II—21.03%, III—14.00%, IV—14.00%, V—7.98%, and VI—13.97%. DOI 10.1002/jps

RESULTS AND DISCUSSION Assignment of SS Spectra 13

C CPMAS NMR spectra were recorded for pure carvedilol form II and for a series of tablets containing this substance. The 13 C CPMAS NMR spectra of solid pure carvedilol form II are illustrated in Figure 2. The 13 C chemical shifts for solid carvedilol form II, as well as the differences δ = δsolution − δsolid state > 1.0 ppm are included in Table 1. The assignment of signals of carvedilol form II in the solid phase spectrum was based on solution chemical shifts20 and DD experiments. DD experiments were particularly helpful in assigning the resonances in 13 C CPMAS spectra of solid carvedilol, as the spectra display signals arising from quaternary carbon atoms, even though signals from carbon atoms in mobile environments, such as methyl ones, are present too. Introducing 50 :s delay before acquisition results in the selective dephasing of methine and methylene carbon atoms, whereas the resonances of quaternary carbon atoms remain intense (Fig. 2). Quaternary carbon atoms in JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 5, MAY 2012

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Figure 5. 13 C CPMAS NMR spectra of carvedilol tablets: IV —Carvedilol-ratiopharm 25 (Ratiopharm), V—Carvedigamma 25 (W¨orwag Pharma), and VI—Vivacor 25 (Anpharm). (Signals of the excipients are marked with color letters: red K—crospovidone, green L—lactose, blue C—cellulose, pink LNa—sodium lauryl sulfate.)

the range 135–155 ppm could be assigned by comparison with their solution counterparts. Although the sequence of resonances in SS spectra generally follows that in solution spectra, inspection of Table 1 reveals some chemical shift differences. Chemical shifts of carvedilol can be modified by twisting the aromatic rings, rotation around C C bonds of the aliphatic chain, reorientation of the OCH3 group, as well as the formation of hydrogen bonds involving OH and NH groups. Drug Formulations Solid-state 13 C CPMAS NMR provides the possibility to characterize the form of carvedilol as well as to compare the formulations from different manufacturers. The 13 C CPMAS NMR spectra of pharmaceutical preparations containing carvedilol (I)–(VI) are shown in Figures 3–5. 13 C NMR chemical shifts (δ, ppm) for excipients in these solid samples are collected in Table 2. The SSNMR spectra of tablets are similar to the spectra of the respective pure substances and appeared to be like the superimposed pattern of the JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 5, MAY 2012

SSNMR spectra of carvedilol form II and those of the excipients used for the formulation (Fig. 3). Analysis of 13 C chemical shifts of carvedilol in preparations I–VI revealed that δ = δpure carv − δcarv preparation for particular carbon atoms do not exceed 0.2 ppm. No significant differences in carvedilol chemical shifts were observed among the reference sample and each of the six tablet formulations. This strongly suggests that all producers use the same crystalline form of the active substance and indicates that carvedilol freebase form II is the active ingredient in each formulation. The above results show that (1) in the studied products, carvedilol exists in crystalline form II and not as amorphous or polymorphic solid, and (2) there are no strong intermolecular interactions between the carvedilol molecules and the excipients in the tablets. The tablet spectra were recorded with slightly longer contact times (4–5 ms), and benefit from the faster 1 H T1ρ relaxation rates of the excipients, relative to carvedilol. In addition, carbohydrates such DOI 10.1002/jps

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Table 2. 13 C CPMAS NMR Chemical Shifts (δ, ppm) of the Pure Excipients and as Components of Pharmaceutical Preparations I–VI δ [ppm] Crospovidone

δ [ppm] I–V

176.1 32.8 18.6 42.7 42.7 32.8

175.2–176.3 32.7–33.0 18.2–18.6 42.4–43.0 42.4–43.0 32.7–33.0

1 2/2 3/5 4 6/6 1 3 /5 4

Lactose 106.6 72.0 74.1 68.8 61.3 92.2 70.8 86.7

I–VI 106.5–106.7 72.1a –72.3 74.1–74.3 68.9–69.1a 61.3–61.6 92.2–92.5a 70.8–71.0a 86.6–86.9

1 2/3/5 4/4 6/6

Cellulose 104.9 74.8/72.1 88.7/84.1 64.9/62.0

VI 104.9a 74.3/72.2a 88.8/84.2a 65.1/62.2

Carbon Atom 2 3 4 5 1 2

a Signals

Carbon Atom

δ [ppm] Sodium Lauryl Sulfate

δ [ppm] VI

1 2–9 10 11 12

69.0 33.0 28.0 24.5 14.7

69.1a 33.1 27.9 24.3 14.4

1 2 3/3 4 5 6 1 2 4 5 6

Saccharose 92.6 71.2 73.1 67.4 81.1 60.6 59.3 82.3 72.1a 101.9 65.3

I, II 92.5a 71.0a 73.1 67.4 81.1 60.6 59.3 82.3 72.1a –72.2 101.9 65.3

partly or completely overlapped.

as lactose and saccharose have much longer 1 H T1 relaxation times than carvedilol, and their signals are additionally suppressed in the tablet spectra. The resonances of lactose, saccharose, and cellulose appear within 65–105 ppm, that is, the region typical of carbohydrates, and can be easily recognized. All examined formulations contained lactose; in II and VI, lactose is the main filler and occurs in large amounts. Distinct signals of lactose appear at 61.4 (C6/6 ), 86.7 (C4), 92.2, and 106.5 ppm (C1/1 ) and the group of other resonances at 68.9–74.1 ppm. In tablets I and V, the main fillers were saccharose and cellulose, respectively, and lactose was added in smaller amounts. Tablets III and IV contained mixtures of lactose and saccharose. Crospovidone (cross-linked polyvinyl pyrrolidone) was used as a disintegrant (I–V), a substance swelling in aqueous solution and hereby causing a tablet to break apart into smaller fragments. Intense signals of crospovidone appear at 18.6, 32.8, 42.7, and 176.1 ppm, that is, outside the spectral region of carvedilol. Only in Vivacor 25 (Anpharm) (VI), sodium lauryl sulfate was used as a disintegrant and a tenside (lowering surface tension and enabling water diffusion inside the tablet). Inspection of the 13 C CPMAS NMR spectra (illustrated in Figs. 3–5) shows that they are useful for fast identification of the type of excipient/excipients, as well as for establishing their relative content in tablets from different sources. The spectra were DOI 10.1002/jps

recorded under constant measuring conditions and with the same number of scans (ns = 1000). The differences in carvedilol’s signal intensities are due to different concentrations of drug substance in tablets mass because the tablets differ in size. The highest carvedilol concentration (30%) occurs in Dilatrend 25 (Roche) (I), the lowest one in Carvedigamma 25 (W¨orwag Pharma) (V) (8%). The remaining tablets contain 21% (II) or 14% (III, IV, VI) of the active substance in tablet mass. Quantitation of Carvedilol in Drug Formulations In pharmaceutical industry, there is considerable interest in quantifying the formulated products, and so an approach to quantitative analysis using SSNMR can be valuable. NMR is by definition a quantitative technique because the intensity of a resonance signal is directly proportional to the number of resonant nuclei. However, a validated protocol for quantitative high-resolution solution 1 H NMR was not described until 2005.21 Despite limited accuracy to date, quantitative 13 C NMR in liquids is used in pharmacy and material sciences, where purity or content determinations of substances are the key issues. In order to achieve quantitative or near-quantitative 13 C CPMAS NMR of organic materials, there are a number of important phenomena to consider, particularly the CP kinetics of each component of interest.22 A protocol for SSNMR quantitation may include13 the following: spectrometer settings, data processing, measuring JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 5, MAY 2012

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the rotating frame: −1

H H ) [exp(−t/T1ρ ) − exp(−t/TCP )] I(t) = I0 (1 − TCP /T1ρ

Figure 6. CP kinetics for C4 (quaternary carbon atom, δ 154 ppm), C2 (protonated carbon atom, δ 129 ppm), and C9 (methyl carbon atom δ 53 ppm). Fitting was performed using the I–S model.

the peak area, constructing a plot of composition versus peak area, and error analysis. Spectrometer settings and data processing were the same for all measurements. The appropriate relaxation delay (D1 = 10 s) was established in a separate experiment, running the spectra with a set of recycle delays. The CP experiment provides evident 13 C signal enhancement and reduction of the measurement time, with the only drawback being that CP kinetics must be considered for quantitation. The intensities of signals can be compared after examining their CP kinetics. In order to obtain the intense resonances of the most informative signals, a series of spectra with contact time t in the range 25 :s–20 ms were recorded. It is frequently assumed that quaternary carbon atoms and rotating methyl groups cross-polarize according to the classical I–S model. Within this model, the intensity I(t) initially rises according to time constant TCP , and then decreases according to another time constant TH 1ρ , the 1 H spin relaxation time in JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 5, MAY 2012

The peak areas must be compared on the basis of absolute intensities I0 obtained from fittings of the kinetic results. The contact time of 1–3 ms is most frequently applied to organic solids. However, rotating methyl groups and quaternary carbon atoms may need longer times. Maximum intensity of the quaternary carbon resonances was obtained with t = 5–6 ms, as illustrated for C4 (Fig. 6). Experimental data were fitted to the I–S model, and CP kinetic parameters TCP and TH 1ρ (ms) for pure carvedilol form II are included in Table 1. The TCP values are 0.3–0.6 ms for aromatic CH carbon atoms, and less than of approximately 0.2 ms for methylene carbon atoms, as expected. TCH of 1–2.2 ms reflect slower build up of magnetization for quaternary carbon atoms. The CP experiments on organic compounds frequently afford a single TH 1ρ value. The TH 1ρ values for quaternary carbon atoms of carvedilol are of 400– 420 ms, that is, two to four times longer than for protonated ones, reflecting the differences in relaxation and spin diffusion. Long TH 1ρ are observed for mobile systems (functional groups); the values of TH 1ρ = 320 ms and TCP = 0.43 ms for C9 indicate fast rotation of the methyl group. Variable contact time experiments were necessary to find “perfect” contact time, which ensures quantitation for the carbons of interest (outside the region overlapped by the resonances of cellulose). All wellseparated signals were used for quantitative measurements. The peaks chosen for the analysis are those of: carbonyl carbon atom C4 ; two quaternary carbon atoms C3 and C4 (phenyl moiety); the common peak of two quaternary carbon atoms proximal to nitrogen atom, that is, C11 and C12 ; two protonated carbon atoms C2 and C9 (carbazole moiety); as well as methyl carbon atom C9 . The linear plots of C4 , C11 /C12 , and C2 signal area versus concentration of carvedilol are illustrated in Figure 7. The best choice for quantitation seemed to be C2 , the resonance at 129.5 ppm is given by one carbon atom and R2 = 0.9989 proves that all parameters in the spectra of I–VI were set properly. Satisfactory results were also obtained for the three quaternary carbon atoms C4 (154 ppm), C4 (149 ppm), C3 (148 ppm) and for the protonated carbon atom C9 (126 ppm) (R2 = 0.9936, 0.9961, 0.9966, and 0.9966, respectively). The signal at 139 ppm comes from two carbon atoms C11 and C12 bound to nitrogen atom (separated by 0.2 ppm in solution spectrum). The linkages to quadrupolar neighbor result in slightly broader resonance in the SSNMR spectrum. An advantage is that this signal DOI 10.1002/jps

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Figure 7. Signal intensity of (a) C 4 (δ = 154 ppm), (b) C11 /12 (δ = 139 ppm), and (c) C2 (δ 129 ppm) in the 13 C CPMAS spectra versus carvedilol form II content (%) in the formulations I–VI. One hundred percent carvedilol content refers to pure compound sample.

appears in the “empty” spectral region, 130–145 ppm, without the resonances of excipients. As a result, the correlation plot with R2 = 0.9911 is acceptable. In order to use the C9 (OMe) resonance at 53.5 ppm, the deconvolution of the spectral lines was necessary, as it is partially overlapped by that of C3 at 51.5 ppm. Nevertheless, the calculated intensities were used to DOI 10.1002/jps

construct a plot, and a linear relationship with R2 = 0.9885 was obtained. An attempt to quantify carvedilol in solid formulations I–VI appears to be quite satisfactory; the results make it possible to estimate the concentration of the active substance. While performing a quantitative experiment one needs a compromise, either to use more JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 5, MAY 2012

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samples for a calibration plot or to run the spectra with a larger number of scans because the total spectrometer time for the analysis should not be longer than 1–2 days.

CONCLUSION SSNMR spectroscopy showed that carvedilol in tablets exists as crystalline solid and the form II is the same in all studied commercial drugs. Such information is important for the development of the oral dosage form. In this study, SSNMR spectroscopy was proven to be a powerful technique for evaluating the SS formulations of carvedilol with different excipients. Using the spectra of commercial drugs as a “fingerprint” only, one can easily distinguish the preparations. A detailed analysis of the SS spectra of the preparations and the development of measurement procedures yielded quantitative data that are in agreement with the specification of producers. Our results show that quantitative analysis can be performed on any carbon atom giving a well-separated 13 C NMR signal (nonoverlapped by excipient). Using a protocol for the quantitative approach, SSNMR was accurate for compositional characterization of powdered tablets of carvedilol.

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