Solid-State Investigations of Erythromycin A Dihydrate: Structure, NMR Spectroscopy, and Hygroscopicity

doi:10.1021/js9701667

Journal of Pharmaceutical Sciences

Volume 86, Issue 11, November 1997, Pages 1239-1244

https://doi.org/10.1021/js9701667 Get rights and content

Abstract

The crystal structures of the commercially available form of erythromycin A dihydrate and clarithromycin anhydrate, in addition to the structure of erythromycin B dihydrate, are reported in this paper. In light of the crystallographic data, analysis of the structural information provides insight into the physical properties of these pharmaceuticals. The propensity of these pharmaceuticals to form solvated structures is discussed and the hygroscopicity of erythromycin A dihydrate is investigated. Solid-state ¹³C NMR was used to monitor changes that occur when the dihydrate form of erythromycin A is stored under conditions of low relative humidity. Although erythromycin A dihydrate retains its crystallographic order at low humidity, as indicated by its X-ray powder diffraction pattern, the local chemical environment is dramatically influenced by the loss of the water molecules and results in dramatic changes in its solid-state ¹³C NMR spectrum.

References and Notes (19)

J. Bauer et al.
Pharm. Sci.
(1985)
P.V. Allen et al.
Pharm. Sci.
(1978)
G.A. Stephenson
Solid-State Investigations of Selected Pharmaceutical Compounds
(1994)
G.A. Stephenson et al.
Am. Chem. Soc.
(1994)
G.M. Sheldrick
SHELX86
(1986)
MolEN
An Interactive Structure Solution Procedure, Enraf Nonius, Delft
(1990)
R.C.G. Killean et al.
Acta Crystallogr
Sect.
(1750–1752)
International Tables for X-ray Crystallography
Table 2.2B, vol. 4, p. 99, and Table 2.3.1, vol. 4, p. 149
(1974)
J.A. Ibers et al.
Acta Crystallogr.
(1964)

There are more references available in the full text version of this article.

Cited by (87)

Hydrates of active pharmaceutical ingredients: A <sup>35</sup>Cl and <sup>2</sup>H solid-state NMR and DFT study
2022, Solid State Nuclear Magnetic Resonance
This study uses ³⁵Cl and ²H solid-state NMR (SSNMR) spectroscopy and dispersion-corrected plane-wave density functional theory (DFT) calculations to characterize the molecular-level structures and dynamics of hydrates of active pharmaceutical ingredients (APIs). We use ³⁵Cl SSNMR to measure the EFG tensors of the chloride ions to characterize hydrated forms of hydrochloride salts of APIs, along with two corresponding anhydrous forms. DFT calculations are used to refine the crystal structures of the APIs and determine relationships between the ³⁵Cl EFG tensors and the spatial arrangements of proximate hydrogen bonds, which are particularly influenced by interactions with water molecules. We find that the relationship between ³⁵Cl EFG tensors and local hydrogen bonding geometries is complex, but meaningful structure/property relationships can be garnered through use of DFT calculations. Specifically, for every case in which such a comparison could be made, we find that the hydrate has a smaller magnitude of C_Q than the corresponding anhydrous form, indicating a chloride ion environment with a ground-state electron density of higher spherical symmetry in the former. Finally, variable-temperature ³⁵Cl and ²H SSNMR experiments on a deuterium-exchanged sample of the API cimetidine hydrochloride monohydrate are used to monitor temperature-dependent influences on the spectra that may arise from motional influences on the ³⁵Cl and ²H EFG tensors. From the ²H SSNMR spectra, we determine that the motions of water molecules are characterized by jump-like motions about their C₂ rotational axes that occur on timescales that are unlikely to influence the ³⁵Cl central-transition (+1/2 ↔︎ −1/2) powder patterns (this is confirmed by ³⁵Cl SSNMR). Together, these methods show great promise for the future study of APIs in their bulk and dosage forms, especially variable hydrates in which crystallographic water content varies with external conditions such as humidity.
Insights into the ethanol solvate form of clarithromycin
2022, Journal of Molecular Structure
Citation Excerpt :
Note the signal assigned to ethanol CH2 present in the NQS spectrum (Fig. 2D) (that should display only methyl or quaternary carbons). This fact arises from the high thermal motion of the solvent molecule (as expressed Jin et al. [33]) that produces an average of the dipolar interaction in CH2 moiety. The sharpness of signals in CAM-0 gave evidence that there are no visible residues of commercial CAM form II.
Some polymorphic drugs may undergo solid-state transformations as a result of storage and manufacturing processes, which could have a significant impact on the performance characteristics of the drug. The present study was conducted as a strategy to provide information on clarithromycin polymorphs. The exhaustive characterization of solid form 0, an ethanol solvate, was performed starting with the development of a new synthesis route. The structural characterization was carried on by comparing the form 0 with the form II, the one currently used on the market. A variety of techniques, such as solid state nuclear magnetic resonance, X-ray powder diffraction, infrared spectroscopy, thermoanalytical methods and confocal microscopy, were used to identify the form 0. These studies revealed important intermolecular interactions, as well as certain spatial and morphological particularities. The biopharmaceutical properties including solubility in water and simulated gastric fluid, and microbiological performance were investigated. The physical stability under normal storage conditions during 15 months was examined, revealing a desolvation process and a subtle polymorphic transformation. The studies performed on the ethanol solvate of clarithromycin could prove to be a useful tool for assays used to ensure that the drug quality remains without changes in the final dosage product.
Polymorphism and its Implications in Pharmaceutical Product Development
2018, Dosage Form Design Parameters
Most of the pharmaceutical products are solids; therefore, the knowledge of solid-state characteristics of any active pharmaceutical ingredients (APIs) and excipients is vital for their development as a successful drug product. Knowledge of the physical and chemical properties such as solubility and stability of materials during the initial stages of drug development helps to prevent the difficulties in their manufacturing and moreover improve their quality. Hence, the understanding of polymorphism and crystal behavior of any pharmaceutically relevant materials is highly required. Polymorphism is the property of solid materials to exist in two or more crystalline forms with different conformations or orientations of the components in the crystal lattice. The polymorphs of a material may vary in their physicochemical characteristics, such as dissolution, solubility, stability, and hygroscopicity, etc. Polymorphs may also differ in other important drug aspects like efficacy, bioavailability, and toxicity. Thus, a particular property of a polymorph might not be exhibited by another polymorph of same material. This chapter will deal with all the aspects of polymorphism which include the theories, preparation, characterization, and their pharmaceutical importance.
Solid-state characterization and techniques
2017, Developing Solid Oral Dosage Forms: Pharmaceutical Theory and Practice: Second Edition
Solid-state characterization allows scientists to understand the properties of formulation and formulation components, the first step in rational formulation development. Analytical technique measures response(s) to perturbation(s) of the objects under examination. The perturbation could be thermal, mechanical, light, radio frequencies, electromagnetic fields, or a combination thereof. Information extracted from their responses allows one to infer properties of the objects. It is therefore important to probe a system of interest from different angles, and it is the combined knowledge that forms a more comprehensive understanding of the system. This is particularly important for pharmaceutical solids, where the slow molecular mobility and heterogeneity results in weaker and variable responses. This chapter highlights some of the basic characterization tools for pharmaceutical solids, including microscopy (optical, electron, and probe microscopy), power X-ray diffraction, thermal analysis (differential scanning calorimetry, thermogravimetric analysis, and microcalorimetry), vibrational spectroscopy (infrared, Raman), solid-state NMR, moisture sorption and highlights some hyphenated techniques. The aim is to familiarize pharmaceutical scientists with the basic principles and typical applications of these commonly employed analytical tools for characterization of pharmaceutical solids.
Azithromycin hydrates-implications of processing-induced phase transformations
2014, Journal of Pharmaceutical Sciences
According to label claims, in commercial solid dosage forms, azithromycin (AZI) exists either as a monohydrate (MH) or as a dihydrate (DH). Although these two forms are known to be relatively stable in the solid state, AZI sesquihydrate (SH) was observed in a drug product. This was believed to be a consequence of a processing‐induced phase transformation. Our goal was to prepare and characterize AZI SH and map its solid‐state transition pathways with other AZI phases. When dehydrated at temperatures <80°C, DH yielded an isomorphic dehydrate, whereas dehydration at ≥80°C yielded SH. Heating SH to 100°C or holding at 0% RH at room temperature, yielded an amorphous product through an intermediate isomorphic dehydrate, isostructural to SH. On the other hand, dehydration of MH (at ≥60°C) resulted in amorphization with no intermediate crystalline anhydrate. Diagnostic XRD peaks of AH, MH, SH, and DH enabled their unambiguous identification. However, the presence of crystalline excipients hindered active pharmaceutical ingredient characterization in drug product. Pattern subtraction method was used to selectively remove the contribution of the crystalline excipients to the overall diffraction pattern, thereby facilitating the physical characterization of AZI in the drug product. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3095–3106, 2014
Structural studies of a non-stoichiometric channel hydrate using high resolution X-ray powder diffraction, solid-state nuclear magnetic resonance, and moisture sorption methods
2014, Journal of Pharmaceutical Sciences
Structural investigations of a nonstoichiometric hydrate, AMG 222 tosylate, a DPP‐IV inhibitor in clinical development for type II diabetes, were performed using a multitechnique approach. The moisture sorption isotherm is in good agreement with a simple Langmuir model, suggesting that the hydrate water is located in well‐defined crystallographic sites, which become vacant during dehydration. Crystal structures of AMG 222 tosylate at ambient and dry conditions were determined from high‐resolution X‐ray diffraction using the direct space method. On the basis of these crystal structures, hydrated water is located in channels formed by the drug framework. Upon dehydration, an isostructural dehydrate is formed with the channels remaining void and accessible to water for rehydration. Kitaigorodskii packing coefficients of the solid between relative humidity of 0% and 90% indicate that the equilibrium form of AMG 222 tosylate is the fully hydrated monohydrate. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2809–2818, 2014

View all citing articles on Scopus

View full text

Solid-State Investigations of Erythromycin A Dihydrate: Structure, NMR Spectroscopy, and Hygroscopicity

Abstract

Pharm. Sci.

Pharm. Sci.

Solid-State Investigations of Selected Pharmaceutical Compounds

Am. Chem. Soc.

SHELX86

An Interactive Structure Solution Procedure, Enraf Nonius, Delft

Acta Crystallogr

Sect.

Table 2.2B, vol. 4, p. 99, and Table 2.3.1, vol. 4, p. 149

Acta Crystallogr.