Łukasz Szeleszczuk

13C solid-state NMR analysis of the most common pharmaceutical excipients used in solid drug formulations, Part I: Chemical shifts assignment

Solid-state NMR is an excellent and useful method for analyzing solid-state forms of drugs. In the (13)C CP/MAS NMR spectra of the solid dosage forms many of the signals originate from the excipients and should be distinguished from those of active pharmaceutical ingredient (API). In this work the most common pharmaceutical excipients used in the solid drug formulations: 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. Their (13)C CP/MAS NMR spectra were recorded and the signals were assigned, employing the results (R(2): 0.948-0.998) of GIPAW calculations and theoretical chemical shifts. The (13)C ssNMR spectra for some of the studied excipients have not been published before while for the other signals in the spectra they were not properly assigned or the assignments were not correct. The results summarize and complement the data on the (13)C ssNMR analysis of the most common pharmaceutical excipients and are essential for further NMR studies of API-excipient interactions in the pharmaceutical 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.

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.

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).

In Vitro Dissolution of Calcium Carbonate from the Chicken Eggshell: A Study of Calcium Bioavailability

In vitro dissolution is a major indicator of potential in vivo calcium absorption. It can be used to assess the bioavailability of Ca from different sources. The aim of this study was to analyze the in vitro dissolution of calcium carbonate from the eggshell samples collected before and after the incubation period. The samples of chicken eggshell were characterized by good dissolution, better than that of precipitated CaCO3. The dissolution of the eggshell before incubation was found to be faster than that after incubation. Good dissolution (after 30 min both types of eggshells were dissolved in over 75%) of the chicken eggshell and the presence of other valuable microelements (boron, strontium) make this biomaterial an excellent source for dietary supplements production.

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.

Analysis of Water in the Chicken Eggshell Using the 1H Magic Angle Spinning Nuclear Magnetic Resonance Spectroscopy

ABStRACt The water content of the chicken eggshell has a major influence on gas (CO 2 and O 2 ) permeability. Inappropriate water loss during the incubation period increases embryo mortality and decreases chick quality. So far only the procedures that enable to determine the total water content in the eggshell have been described and developed. Our analysis of the 1 H MAS NMR spectra of the chicken eggshell samples revealed three signals, differing significantly in the chemical shift and relaxation times (T1) parameters. In this work we have assigned those signals and described the changes in their intensities that occur during the incubation period. Using 1 H MAS NMR it is possible to distinguish two types of water reservoirs in the chicken eggshell. This approach can be used for more detailed analysis of the water content in the eggshells. IntRoduCtIon Chicken eggshell (CE) is a complex structure consisting of an organic matrix and minerals, particularly calcium carbonate in the polymorphic form of calcite (Dennis

Influence of acetylation on anomeric effect in methyl glycosides

abstract In the following research acetylation as an unexplored factor in the anomeric effect in carbohydrate chemistry has been examined. Crystallographic data for methyl glycosides and their acetates have been compared and discussed. Some of the methyl glycosides form hydrogen bonding with the participation of acetal oxygen atoms. This seems to have the most significant influence on the structural diagnostic parameters for anomeric effect. Abbreviations: Me-α-Glc: methyl α-D-glucopyranoside; Me-β-Glc: methyl β-D-glucopyranoside; Me-α-Gal: methyl α-D-galactopyranoside; Me-β-Gal: methyl β-D-galactopyranoside; Me-α-Man: methyl α-D-mannopyranoside; Me-β-Man: methyl β-D-mannopyranoside; Ac-Me-α-Glc: methyl 2,3,4,6-tetra-O-acetyl-α-D-glucopyranoside; Ac-Me-β-Glc: methyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside; Ac-Me-α-Gal: methyl 2,3,4,6-tetra-O-acetyl-α-D-galactopyranoside; Ac-Me-β-Gal: methyl 2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside; Ac-Me-α-Man: methyl 2,3,4,6-tetra-O-acetyl-α-D-mannopyranoside; Ac-Me-β-Man: methyl 2,3,4,6-tetra-O-acetyl-β-D-mannopyranoside; GIPAW (Gauge Including Projector Augmented Waves) calculations: a DFT based method used for calculating nuclear magnetic resonance parameters; CP/MAS NMR: cross-polarisation (CP) magic angle spinning (MAS) NMR spectroscopy; δss: chemical shift in 13C CP/MAS NMR spectrum; δt: theoretical chemical shift: as derived from GIPAW DFT; dis: distorted multiplet in 1H NMR spectrum. GRAPHICAL ABSTRACT

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.