Azithromycin Hydrates—Implications of Processing‐Induced Phase Transformations

Sundaramurthi, Prakash; Suryanarayanan, Raj

doi:10.1002/jps.24084

Cited by 15 publications

(19 citation statements)

References 31 publications

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“…From the FTIR spectrum ( Figure 13 ), it can be seen that AZI has an O–H stretching vibrational region at 3400 cm −1 , a peak at 3494 cm −1 indicating the presence of “tightly bound” water, and a peak at 3560 cm −1 , indicating the presence of two crystalline water in AZI [ 27 , 28 ], while the polymer does not have a stretching vibrational peak in this region. Meanwhile, for AZI-RL PO, the O–H stretching vibration peak ((3560 cm −1 ) disappeared and only a broad absorption peak (3419 cm −1 ), indicating the loss of AZI crystal water during the HME process and the formation of “loosely bound” water [ 27 ].…”

Section: Resultsmentioning

confidence: 99%

Preparation of Azithromycin Amorphous Solid Dispersion by Hot-Melt Extrusion: An Advantageous Technology with Taste Masking and Solubilization Effects

Li²,

Zhang³

et al. 2022

Polymers

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Azithromycin (AZI) is one of the most commonly used macrolide antibiotics in children, but has the disadvantages of a heavy bitter taste and poor solubility. In order to solve these problems, hot-melt extrusion (HME) was used to prepare azithromycin amorphous solid dispersion. Preliminary selection of a polymer for HME was conducted by calculating Hansen solubility parameter to predict the miscibility of the drug and polymer. Eudragit® RL PO was chosen as the polymer due to its combination of taste-masking effect and dissolution. Moreover, the solubility was improved with this polymer. Design of experiments (DoE) was used to optimize the formulation and process, with screw speed, extrusion temperature, and drug percentage as independent variables, and content, dissolution, and extrudates diameter as dependent variables. The optimal extrusion parameters were obtained as follows: temperature—150 °C; screw speed—75 rpm; and drug percentage—25%. Differential scanning calorimetry (DSC) and Powder X-ray Diffraction (PXRD) studies of the powdered solid dispersions showed that the crystalline AZI transformed into the amorphous form. Fourier transform infrared spectroscopy (FTIR) results indicated that the formation of a hydrogen bond between AZI and the polymer led to the stabilization of AZI in its amorphous form. In conclusion, this work illustrated the importance of HME for the preparation of amorphous solid dispersion of AZI, which can solve the problems of bitterness and low solubility. It is also of great significance for the development of compliant pediatric AZI preparation.

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Section: Resultsmentioning

confidence: 99%

Preparation of Azithromycin Amorphous Solid Dispersion by Hot-Melt Extrusion: An Advantageous Technology with Taste Masking and Solubilization Effects

Li²,

Zhang³

et al. 2022

Polymers

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“…3b), heated at 10 K min -1 , exhibited a visible absence of any dehydration and melting events. A baseline discontinuity (Heat capacity change (DC p ) = 0.48 J g -1 K -1 ), attributed to the glass transition (T g ), was observed at 380.9 K. This was higher than the reported T g of 367 K from Sundaramuthi et al [13]. The hygroscopicity (Fig.…”

Section: Azm Amorph I and Hygroscopicitymentioning

confidence: 65%

“…For hydrogen atoms, the largest deviation of 0.109 A ˚occurred for H13A of one of the water molecules. Sundaramurthi and Suryanarayanan [13] demonstrated with diagnostic powder XRD analysis that AZM-DH converted to a sesquihydrate crystal phase at 353 K, which transformed back to the AZM-DH crystal at 313 K in the presence of humidity (15% RH). The validation of the dihydrate crystal phase at ambient temperature suggested that some structural stability existed at 353 K. This stability (Fig.…”

Section: Structural Data and Physical Stabilitymentioning

confidence: 99%

“…The reported melting enthalpies (30-45 J g -1 ) [11] of the anhydrous phase, prepared by thermal dehydration of AZM-DH in the vicinity of 373 K as well as extreme humidity storage at 0% RH, did elude to crystallinity but to what extent is unknown. Timoumi et al [12] concluded that AZM-DH converted to an isomorphic dehydrate at 353 K. Sundaramurthi and Suryanarayanan [13] reported that the temperature for complete thermal dehydration of AZM-DH influenced the crystallinity of the produced anhydrous form. Temperatures between 333 and 343 K favoured the formation of a crystalline anhydrate isomorphic to the AZM-DH crystal phase, whereas 353 K produced a crystalline anhydrate isomorphic to a sesquihydrate crystal phase, respectively.…”

Section: Introductionmentioning

confidence: 99%

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Water and the relationship to the crystal structure stability of azithromycin

Neglur

Aucamp

Liebenberg

et al. 2018

J Therm Anal Calorim

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This study investigated the solid-state physical stabilities of azithromycin dihydrate (AZM-DH), thermally prepared anhydrate and hemihydrate modifications. Programmed thermal treatment of AZM-DH in DSC yielded the formation of anhydrate amorphs (I, II), crystalline AZM anhydrate and hemihydrate phases. The formation of the anhydrate amorphs, I and II, respectively, involved different transformation pathways of solid-liquid-solid (melting and supercooling) and solid-solid (378 K for 24 h.). Both amorph phases exhibit hygroscopic behaviour, producing non-stoichiometric hydrates, with extent of moisture absorption increasing with increased storage humidity (0-96% RH/313 K). TG analysis after controlled storage (4 days at 96% RH/313 K) detected absorbed waters of hydration up to 5.9 and 5.3% for amorphs I and II, respectively. The crystal anhydrate and hemihydrate phases were hygroscopic and readily converted to the stoichiometric dihydrate form, which was compositionally stable in RH ranges from 11 to 96% at 313 K. Solubility studies, performed in distilled water at 310 K, showed an at least 1.5 fold solubility improvement for both amorph forms relative to crystalline AZM-DH, but with some evidence of solvent-mediated phase transformation after 20 min. Structural characterization by single-crystal XRD concluded that thermally stimulated amorphization required energy to disrupt intermolecular hydrogen bond interactions by bridging water molecules in addition to hydrogen bond interactions between neighbouring AZM molecules in unit cell.

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“…According to the difference in water content, azithromycin has four major crystal forms: dehydrates, monohydrates, dihydrates [5][6][7] and sesquihydrates existing under certain conditions. 8 In commercially available solid formulations, azithromycin mainly exists in the form of dihydrate crystals produced in a mixture of acetone and water. 9 The dilution crystallization of azithromycin is a very interesting but challenging industrial process.…”

Section: Introductionmentioning

confidence: 99%