Physical Characterization of Erythromycin: Anhydrate, Monohydrate, and Dihydrate Crystalline Solids

Allen, Patrick; Rahn, Paul D.; Sarapu, Allen C.; Vanderwielen, A.J.

doi:10.1002/jps.2600670816

Cited by 54 publications

(27 citation statements)

References 13 publications

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“…However, the lack of the crystal structural data for the NZ octahydrate and pentahydrate precluded the structural explanation of the unusual phenomenon that the thermodynamically most stable state is associated with a lower degree of hydration. Similar phenomena were previously reported for erythromycin by Allen et al 26 and for morizicine hydrochloride by Wu et al 27 and were not explained. During the crystallization of a salt hydrate, precipitation of a metastable phase often occurs first followed by a phase transformation to the stable hydrate (Ostwald's rule of stages).…”

Section: Resultssupporting

confidence: 81%

Physicochemical Characterization of Nedocromil Bivalent Metal Salt Hydrates. 2. Nedocromil Zinc

Zhu¹,

Padden²,

Munson³

et al. 1997

Journal of Pharmaceutical Sciences

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Salts are usually considered as alternatives for drug delivery when the physicochemical characteristics of the acidic or basic parent drug are unsuitable or inadequate for a satisfactory formulation. The physical, chemical, and biological characteristics of nedocromil sodium, which is used in the treatment of reversible obstructive airways diseases such as asthma, can be altered by its conversion to other salt forms. Nedocromil zinc (NZ), a bivalent metal salt, was found to exist in several hydration states, an octahydrate, a heptahydrate, and a pentahydrate, which itself exists in two modifications, designated as A and B. The relationships between these, NZ hydrates and the nature of the water interactions in the solid phases were studied through characterization by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Karl Fischer titrimetry (KFT), hot-stage microscopy (HSM), ambient- or variable-temperature powder X-ray diffraction (PXRD), Fourier-transform infrared (FTIR) spectroscopy, solid-state nuclear magnetic resonance (SSNMR) spectroscopy, environmental scanning electron microscopy (ESEM), water uptake at various relative humidities (RH), intrinsic dissolution rate (IDR), and solubility measurements. The integral water stoichiometries of the NZ hydrates were deduced from KFT and TGA and were confirmed by elemental analysis. For the heptahydrate, the loss of 1 mol of water at a higher temperature than for the others is attribute to an identifiable water molecule that is linked directly to the zinc and to two carboxylate oxygen atoms but not to the other water molecules, as deduced from the crystal structure previously determined. Similarly, for both pentahydrate modifications, 1 mol of water was also lost at a higher temperature than the others. Results from studies using DSC, TGA, HSM, PXRD, SSNMR, and FTIR suggested that the octahydrate contains loosely bound water in its structure and is partially amorphous. The course of the dehydration processes depended on the water vapor pressure and temperature. The octahydrate and heptahydrate underwent an apparently irreversible phase transformation to the pentahydrate at an elevated temperature and water vapor pressure. Pentahydrate modifications A and B differ in their long-range order (deduced from differences in their PXRD pattern and their thermal analytical behavior), but their short-range order (i.e., molecular environments) are identical (deduced by identical SSNMR spectra). The rank order of both IDR and solubility in water at 25 degrees C was octahydrate > heptahydrate > pentahydrate modification A approximately pentahydrate modification B, corresponding to the rank order of free energy with respect to the aqueous solution and the order of preparation according to Ostwald's rule of stages.

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Section: Resultssupporting

confidence: 81%

Physicochemical Characterization of Nedocromil Bivalent Metal Salt Hydrates. 2. Nedocromil Zinc

Zhu¹,

Padden²,

Munson³

et al. 1997

Journal of Pharmaceutical Sciences

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“…[10][11][12] The pharmaceutically viable forms of erythromycin A are the amorphous form, anhydrous form, and the marketed dihydrate form. Erythromycin B is an active related substance of erythromycin A and also exists in a dihydrate form.…”

Section: Resultsmentioning

confidence: 99%

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

StephensonX

Stowell

Toma

et al. 1997

Journal of Pharmaceutical Sciences

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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.

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“…In other cases, the hydrate form exhibits a more rapid dissolution rate than its anhydrous form: for example, erythromycin dihydrate was found to exhibit a significantly faster dissolution rate than that of monohydrate and anhydrous forms [43,44].…”

Section: Importance Of Solubility On the Bioavailability Of Drugsmentioning

confidence: 99%

Polymorph Impact on the Bioavailability and Stability of Poorly Soluble Drugs

2015

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Drugs with low water solubility are predisposed to poor and variable oral bioavailability and, therefore, to variability in clinical response, that might be overcome through an appropriate formulation of the drug. Polymorphs (anhydrous and solvate/hydrate forms) may resolve these bioavailability problems, but they can be a challenge to ensure physicochemical stability for the entire shelf life of the drug product. Since clinical failures of polymorph drugs have not been uncommon, and some of them have been entirely unexpected, the Food and Drug Administration (FDA) and the International Conference on Harmonization (ICH) has required preliminary and exhaustive screening studies to identify and characterize all the polymorph crystal forms for each drug. In the past, the polymorphism of many drugs was detected fortuitously or through manual time consuming methods; today, drug crystal engineering, in particular, combinatorial chemistry and high-throughput screening, makes it possible to easily and exhaustively identify stable polymorphic and/or hydrate/dehydrate forms of poorly soluble drugs, in order to overcome bioavailability related problems or clinical failures. This review describes the concepts involved, provides examples of drugs characterized by poor solubility for which polymorphism has proven important, outlines the state-of-the-art technologies and discusses the pertinent regulations.

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Physical Characterization of Erythromycin: Anhydrate, Monohydrate, and Dihydrate Crystalline Solids

Cited by 54 publications

References 13 publications

Physicochemical Characterization of Nedocromil Bivalent Metal Salt Hydrates. 2. Nedocromil Zinc

Physicochemical Characterization of Nedocromil Bivalent Metal Salt Hydrates. 2. Nedocromil Zinc

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

Polymorph Impact on the Bioavailability and Stability of Poorly Soluble Drugs

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