Monika Zielińska-Pisklak

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

(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 carvedilols solid formulations.

13C cross-polarization magic-angle spinning nuclear magnetic resonance analysis of the solid drug forms with low concentration of an active ingredient-propranolol case

Solid State NMR is a method that could be widely used for analyzing solid state forms of drugs in their original formulations. However, when the concentration of the active pharmaceutical ingredient (API) in the final drug form is low, (13)C CP MAS NMR methods using standard parameters are not efficient. An example of this situation is propranolol, an important drug from the group of beta-blockers whose concentration in the final drug form is low (below 10%). Basing on the differences in the CP kinetics and relaxation parameters for propranolol and the excipients the authors suggest the proper set of the CP MAS experimental parameters that would allow one to analyze API even in small concentrations in the solid drug formulations.

1H and 13C NMR characteristics of β-blockers.

The β‐blockers are important drugs and decades of clinical experience proved their high medical status. However, to the best of our knowledge, there is no complete assignment of 1H and 13C NMR resonances of popular representatives: acebutolol, alpenolol, pindolol, timolol and propranolol and the published NMR data on carvedilol and atenolol are incorrect. Therefore, 1H and 13C NMR spectroscopy was applied for the characterization of a series of β‐adrenolytics: carvedilol (1), pindolol (2), alprenolol (3), acebutolol (4), atenolol (5), propranolol (6) and timolol (7). Two‐dimensional NMR experiments (COSY, HMQC, HMBC, NOESY) allowed the unequivocal assignment of 1H and 13C spectra for solution (DMSO‐d6). Salts and bases can be easily distinguished based on 13C chemical shifts which are within 65.0–65.5 ppm (OC2) and 46.9–47.0 (NC3) for hydrochlorides and larger, ca. 68.4 ppm (OC2) and 50.3–52.6 (NC3) for bases. NMR data of 1–7 should be included in pharmacopoeias. Copyright

13C solid-state NMR analysis of the most common pharmaceutical excipients used in solid drug formulations Part II: CP kinetics and relaxation analysis

Excipients used in the solid drug formulations differ in their NMR relaxation and (13)C cross-polarization (CP) kinetics parameters. Therefore, experimental parameters like contact time of cross-polarization and repetition time have a major impact on the registered solid state NMR spectra and in consequence on the results of the NMR analysis. In this work the CP kinetics and relaxation of the most common pharmaceutical excipients: anhydrous α-lactose, α-lactose monohydrate, mannitol, sucrose, sorbitol, sodium starch glycolate type A and B, starch of different origin, microcrystalline cellulose, hypromellose, ethylcellulose, methylcellulose, hydroxyethylcellulose, sodium alginate, magnesium stearate, sodium laurilsulfate and Kollidon(®) were analyzed. The studied excipients differ significantly in their optimum repetition time (from 5 s to 1200 s) and T(1ρ)(I) parameters (from 2 ms to 73 ms). The practical use of those differences in the excipients composition analysis was demonstrated on the example of commercially available tablets containing indapamide as an API. The information presented in this article will help to choose the correct acquisition parameters and also will save the time and effort needed for their optimization in the NMR analysis of the solid drug formulations.

Spectroscopic and structural studies of the diosmin monohydrate and anhydrous diosmin

Diosmin, a flavone glycoside frequently used in therapy of various veins diseases in monohydrate form, exhibits poor solubility in water and low bioavailability. Due to the fact that the anhydrous forms of drugs generally have better bioavailability than the corresponding hydrates, the aim of this study was to analyze the conversion of diosmin monohydrate (DSNM) to anhydrous diosmin (DSNA) that occurs upon heating. The mechanism of this transformation was examined as well as advanced structural studies of each form were performed using 13C CP/MAS SSNMR, DSC, FT-IR and PXRD techniques. Spectroscopic findings were supported by CASTEP-DFT calculations of NMR and IR parameters. The pathway of reversible transformation was specified as follows: DSNM upon heating for 24h at temperature up to 110°C losses non-crystalline water and converts into metastable form (DSNM*) that turns into DSNA during heating at temperature 140°C for next 24h. Under room temperature DSNA spontaneously absorbs moisture from air and turns into a DSNM within 72h. The detailed analysis of CP kinetic parameters (T1ρI) revealed presence of metastable, intermediate form of diosmin (DSNM*) and allowed its characterization. The results are essential for further studies comparing dissolution and bioavailability of DSNM and DSNA. The study provided an understanding of the conversion pathway of the diosmin monohydrate into its anhydrate form when it is exposed to increased temperature.

Can we predict the structure and stability of molecular crystals under increased pressure? First-principles study of glycine phase transitions: First-Principles Study of Glycine Phase Transitions

The aim of this study was to determine whether the periodic density functional theory (DFT) calculations can be used for accurate prediction of the influence of the increased pressure on crystal structure and stability of molecular solids. To achieve this goal a series of geometry optimization and thermodynamic parameters calculations were performed for γ‐glycine and δ‐glycine structures at different pressure values using CASTEP program. In order to perform most accurate geometry optimization various exchange‐correlation functionals defined within generalized gradient approximation (GGA): PBE, PW91, RPBE, WC, PBESOL as well as defined within local density approximation (LDA), i.e. CAPZ, were tested. Geometry optimization was carried out using different dispersion correction methods (i.e. Grimme, TS, OBS) or without them. The linear response density functional perturbation theory (DFPT) was used to obtain the phonon dispersion curves and phonon density of states from which thermodynamic parameters, such as: free energy (ΔG), enthalpy (ΔH) and entropy (ΔS) were evaluated. The results of the geometry optimization depend strongly on the choice of the DFT functional. Calculated differences between the free energy of the studied polymorphic forms at the studied pressure values were consistent with experimental observations on their stability. The computations of thermodynamic properties not only confirmed the order of stability of two studied forms, but also enabled to predict the pressure at which this order is reversed. The results obtained in this study have proven that the plane‐wave basis set first principles calculations under periodic conditions is suitable for accurate prediction of crystal structure and stability.

Application of (13)C NMR cross-polarization inversion recovery experiments for the analysis of solid dosage forms.

Solid-state nuclear magnetic resonance (ssNMR) is a powerful and unique method for analyzing solid forms of the active pharmaceutical ingredients (APIs) directly in their original formulations. Unfortunately, despite their wide range of application, the ssNMR experiments often suffer from low sensitivity and peaks overlapping between API and excipients. To overcome these limitations, the crosspolarization inversion recovery method was successfully used. The differences in the spin-lattice relaxation time constants for hydrogen atoms T1(H) between API and excipients were employed in order to separate and discriminate their peaks in ssNMR spectra as well as to increase the intensity of API signals in low-dose formulations. The versatility of this method was demonstrated by different examples, including the excipients mixture and commercial solid dosage forms (e.g. granules and tablets).

Comment on “Trimorphs of a pharmaceutical cocrystal involving two active pharmaceutical ingredients: potential relevance to combination drugs” by S. Aitipamula, P. S. Chow and R. B. H. Tan, CrystEngComm, 2009, 11, 1823

This is a commentary on a paper by S. Aitipamula et al. (CrystEngComm, 2009, 11, 1823–1827) on the detailed analysis of the stability of trimorphic cocrystals involving two pharmaceutically active substances, ethenzamide and gentisic acid.

Structural studies of calcium channel blockers used in the treatment of hypertension - 1H and 13C NMR characteristics of nifedipine analogues.

The 1 H and 13 C NMR spectroscopy in solution was applied to characterize a series of active pharmaceutical ingredients (API) belonging to the class of calcium channel blockers, a group of drug substances extremely sensitive to UV radiation: nifedipine (1), nitrendipine (2), nisoldipine (3), nimodipine (4), nilvadipine (5), felodipine (6) isradipine (7) nicardipine (8) and amlodipine besylate (9). Two-dimensional NMR experiments (COSY, HSQC, HMBC) allowed the unequivocal assignments of peaks in the 1 H and 13 C spectra in solution and in some cases enabled editing of incorrect assignments appearing in the scientific literature. Various nifedipine derivatives can be easily distinguished based on their 13 C chemical shifts. 1 H and 13 C chemical shifts analysis provides fast identification of the drug substance and ensures its stability in the commercial dosage forms from different sources.

Comparison of the analytical methods (solid state NMR, FT-IR, PXRD) in the analysis of the solid drug forms with low concentration of an active ingredient – 17-β-estradiol case

Graphical abstract Figure. No caption available. HighlightsVarious techniques (IR,PXRD,NMR) in the analysis of solid dosage forms were compared.Low dosage pharmaceutical formulations analysis was performed.13C solid state NMR enabled the identification of API in the formulation. ABSTRACT The application of various techniques (FT‐IR, PXRD, ssNMR) in the analysis of solid dosage forms with low concentration of an API (17‐&bgr;‐estradiol hemihydrate, EBHH) was tested. PXRD analysis of Estrofem Mite tablets (EMT) confirmed the presence of the main crystalline excipient, &agr;‐lactose monohydrate. In the PXRD pattern of EMT the strong background from polycrystalline excipients, i.e. hydroxypropylmethylcellulose and corn starch was observed. FT‐IR spectra were characterized by the broad peaks in the 3000–3600 cm−1 region of the O—H stretching modes coming from multiple hydrogen bonds that are present in the structures of the excipients (&agr;‐lactose monohydrate, corn starch) and API. The only technique which unambiguously confirmed the presence of an API in the EMT was solid state NMR. Despite the tabletting process each of the EMT component retained its characteristic features like relaxation time and T1&rgr;I. Due to the possibility of the manipulation in the experimental registration parameters like recycle delay (RD), evolution time (&tgr;) and contact time (CT) it was possible to perform multiple experiments on the same sample of EMT. The most valuable were the inversion recovery CP experiments in which, by setting the proper values of &tgr;, it was possible to selectively observe the signals of the chosen component of the drug formulation. In this study the great potential of solid state NMR in the analysis of solid dosage forms, as the unique technique that combines the possibility of selective observation of the chosen signals with the non destructive character that enables further analysis of the same sample, was confirmed.