Role of an isomorphic desolvate in dissolution failures of an erythromycin tablet formulation

Bauer, John F.; Dziki, Walter; Quick, John

doi:10.1021/js9900102

Cited by 29 publications

(28 citation statements)

References 16 publications

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“…A number of studies on these forms have been reported. [4][5][6][7][8][9][10][11] At the same time, a literature review showed that similar information on commercially marketed lots of Em raw material is often lacking, and significant variations in the physical properties of the bulk drug are encountered among material supplied by some manufacturers and among different lots supplied by the same manufacturer. 6 Additionally, the intricate molecular structure of Em (Figure 1) suggests the variety of possible supramolecular motifs in crystals, resulting in the formation of different polymorphic modifications.…”

Section: -3mentioning

confidence: 99%

Influence of solvents on the variety of crystalline forms of erythromycin

Mirza¹,

Miroshnyk²,

Heinämäki³

et al. 2003

AAPS PharmSci

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Section: -3mentioning

confidence: 99%

Influence of solvents on the variety of crystalline forms of erythromycin

Mirza¹,

Miroshnyk²,

Heinämäki³

et al. 2003

AAPS PharmSci

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“…5 Furthermore, the structural cavities created in a crystal of erythromycin A dihydrate upon water loss during formulation tend to be filled with excipient molecules of magnesium hydroxide, so that the final product fails the dissolution test. 19 Hence, the development of process analytical tools to ensure the appropriate solid state of the drug is clearly requested.…”

Section: Introductionmentioning

confidence: 99%

Insight into Thermally Induced Phase Transformations of Erythromycin A Dihydrate

Miroshnyk

Khriachtchev

Mirza

et al. 2005

Crystal Growth & Design

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Thermal stress that pharmaceutical solids are exposed to during manufacturing can induce various phase transitions in bulk drug substances or excipients, resulting in altered dosage form performance. This paper reports on the thermally induced transformations of a macrolide antibiotic, erythromycin A dihydrate, investigated in situ by variable temperature powder X-ray diffractometry and hot-stage Raman spectroscopy. Erythromycin A dihydrate undergoes dehydration to isomorphic dehydrate, which then melts and recrystallizes to anhydrate. Raman spectroscopy was able to distinguish the two isomorphs of erythromycin A, the dihydrate and the dehydrate, thus offering a potential tool for in-process control of the drying process. The model fitting approach did not provide insight into the solid-state dehydration mechanism. However, the reaction mechanism was presented on the basis of crystal chemistry.

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“…These results also indicate the relative reactivity of the 2 anhydrates to moisture, which has implications for form selection in product development. 23 The importance in differentiating between the desolvate and the anhydrate is also emphasized by the moisture sorption analysis shown in this study. A schematic representation of the behavior of niclosamide, with respect to solvents and RH, is shown in Figure 6.…”

Section: Discussionmentioning

confidence: 62%

Influence of moisture on the crystal forms of niclosamide obtained from acetone and ethyl acetate

Manek¹,

Kolling²

2004

AAPS PharmSciTech

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ABSTRACTof solvated or hydrated crystal forms, crystals in which the solvent molecules occupy regular positions in the crystal lattice, is widespread among compounds of pharmaceutical interest. 4,5 The behavior of pharmaceutical hydrates in response to changes in environmental conditions can have a significant impact on the development process and dosageform performance. The obvious situation that favors the formation of hydrates is recrystallization, using water as a solvent. However, recrystallization using organic solvents can generate a metastable crystal form, which, when exposed to moisture, absorbs water and changes into a hydrate. The water molecule, because of its small size and multidirectional hydrogen bonding capability, is particularly suited to fill structural voids.6 Pfeiffer et al have described such systems wherein the crystalline form is solvated while in equilibrium with a saturated solution and loses most of its solvent upon drying but retains the 3-dimensional structure of the parent solvate. Pfeiffer further refers to the crystals as "desolvated" crystals and emphasizes the need to differentiate them from a truly unsolvated unique structure like the anhydrate. 7 Stephenson et al introduced the term "isomorphic desolvates" as it accurately defines a desolvate that retains the structure of its parent solvate form. They cited several compounds exhibiting such behavior, some of which include cephalexin, cefaclor, erythromycin A, and spirapril hydrochloride. 8 The purpose of this study was to elucidate the formation of crystal hydrates of niclosamide and to delineate the effect of relative humidity on the crystal forms obtained from acetone and ethyl acetate. Recrystallization of niclosamide was performed in the presence and absence of moisture. Two hydrates and their corresponding anhydrates were isolated. The hydrates obtained by the process of recrystallization from acetone (Form I) and that obtained from ethyl acetate (Form II) were classified based on differences in their dehydration profile, crystal structure, shape, and morphology. Crystals obtained in the absence of moisture were unstable, and when exposed to the laboratory atmosphere transformed to their corresponding hydrates. Differential scanning calorimetry thermograms indicate that Form I changes to an anhydrate at temperatures below 100°C, while Form II dehydrates in a stepwise manner above 140°C. This finding was further confirmed by thermogravimetric analysis. Dehydration of Form II was accompanied by a loss of structural integrity, demonstrating that water molecules play an important role in maintaining its crystal structure. Form I, Form II, and the anhydrate of Form II showed no significant moisture sorption over the entire range of relative humidity. Although the anhydrate of Form I did not show any moisture uptake at low humidity, it converted to the monohydrate at elevated relative humidity (>95%). All forms could be interconverted depending on the solvent and humidity conditions. Niclosamide (5-Chloro-N-(2-chloro-4-nitrop...

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Role of an isomorphic desolvate in dissolution failures of an erythromycin tablet formulation

Cited by 29 publications

References 16 publications

Influence of solvents on the variety of crystalline forms of erythromycin

Influence of solvents on the variety of crystalline forms of erythromycin

Insight into Thermally Induced Phase Transformations of Erythromycin A Dihydrate

Influence of moisture on the crystal forms of niclosamide obtained from acetone and ethyl acetate

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