Polymorphic Transformation of Indomethacin during Hot Melt Extrusion Granulation: Process and Dissolution Control

Xu, Ting; Nahar, Kajalajit; Dave, Rutesh H.; Bates, Simon; Morris, Kenneth R.

doi:10.1007/s11095-017-2325-x

Cited by 20 publications

(8 citation statements)

References 22 publications

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“…From the DSC thermograms, the melting points of IM bulk powder and IM microparticles without PVA were 161 °C and 155 °C, respectively. Previous reports suggested that the IM crystal form, showing a peak at 161 °C, was the γ form, and that the IM crystal form showing a peak at 155 °C was the α form [ 27 , 28 ]. The DSC results were also consistent with the results of the XRPD spectrum and the morphological features [ 29 ].…”

Section: Resultsmentioning

confidence: 99%

Formulation Development of Mucoadhesive Microparticle-Laden Gels for Oral Mucositis: An In Vitro and In Vivo Study

et al. 2020

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In order to relieve pain due to oral mucositis, we attempted to develop mucoadhesive microparticles containing indomethacin (IM) and gel preparations with IM microparticles that can be applied to the oral cavity. The mucoadhesive microparticles were prepared with a simple composition consisting of IM and polyvinyl alcohol (PVA). Two kinds of PVA with different block properties were used, and microparticles were prepared by heating-filtration and mixing-drying. From the X-ray powder diffraction patterns, differential scanning calorimetry thermograms, and morphological features of the IM microparticles, IM should exist as polymorphic forms in the microparticles. Rapid drug release properties were observed in the IM microparticles. Increased drug retention was observed in IM microparticles containing PVA, and the IM-NK(50) gel, using a common block character PVA and heating-filtration, showed good long-term drug retention properties. In vivo experiments showing significantly higher drug concentrations in the oral mucosa were observed with IM microparticles prepared by heating-filtration, and the IM-NK(50) gel maintained significantly higher drug concentrations in the oral mucosa. From these results, the IM-NK(50) gel may be useful as a preparation for relieving oral mucositis pain.

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Section: Resultsmentioning

confidence: 99%

Formulation Development of Mucoadhesive Microparticle-Laden Gels for Oral Mucositis: An In Vitro and In Vivo Study

et al. 2020

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“…Crystal data and physical properties of the α and γ polymorphs of indomethacin [8,9,12,[14][15][16]. The interconversion of α-IM to γ-IM, specifically, can occur due to heat, solvent, mechanical action, such as milling, and exposure to the more stable γ form [12,[36][37][38]. This transformation has been reported in several previous studies and it follows Ostwald's rule of phases with the metastable α-form converting to the more stable γ-form [9,39].…”

Section: Introductionmentioning

confidence: 99%

“…The α to γ transition has previously led to limitations in studying α-IM, especially while using thermal analysis techniques [ 7 ]. Interconversion has also caused issues with using α-IM in hot melt extrusion, an emerging technique for downstream API processing [ 37 ]. It has also been suggested that the presence of small amounts of γ-IM can result in the transformation of the α form [ 12 ], indicating that any impurities or γ seeds during production could lead to interconversion and lower the solubility of the final drug products.…”

Section: Introductionmentioning

confidence: 99%

Stabilization of Metastable Indomethacin α in Cellulose Nanocrystal Aerogel Scaffolds

Banerjee

Brettmann

2021

Pharmaceutics

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Indomethacin (IM) is a small molecule active pharmaceutical ingredient (API) that exhibits polymorphism with the γ-form being the most thermodynamically stable form of the drug. The α-form is metastable, but it exhibits higher solubility, making it a more attractive form for drug delivery. As with other metastable polymorphs, α-IM undergoes interconversion to the stable form when subjected to certain stimuli, such as solvent, heat, pH, or exposure to seed crystals of the stable form. In this study, IM was crystallized into cellulose nanocrystal aerogel scaffolds as a mixture of the two polymorphic forms, α-IM and γ-IM. Differential scanning calorimetry (DSC) and Raman spectroscopy were used to quantitatively determine the amount of each form. Our investigation found that the metastable α-IM could be stabilized within the aerogel without phase transformation, even in the presence of external stimuli, including heat and γ-IM seed crystals. Because interconversion is often a concern during production of metastable forms of APIs, this approach has important implications in being able to produce and stabilize metastable drug forms. While IM was used as a model drug in this study, this approach could be expanded to additional drugs and provide access to other metastable API forms.

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“…Different techniques, such as conventional tablet pressing [ 21 ], freeze-drying [ 22 ], hot-melt extrusion (HME) [ 23 ] and melt-adsorption [ 24 ], are employed for manufacturing ODTs, and HME was utilized in this study. HME has been applied to a wide variety of pharmaceutical dosage forms, including granules [ 25 ], pellets [ 26 ], films [ 27 ], tablets [ 28 ] and implants [ 29 ]. It is widely accepted that HME is easy to scale up and operate continuously as a solvent-free and energy-saving approach for the preparation of various pharmaceutical systems [ 30 ]; moreover, HME can not only enhance the solubility and bioavailability of poorly soluble active pharmaceutical ingredients (APIs), it also improves their stability and bitter taste [ 31 ] and is especially suitable for preparing ODTs.…”

Section: Introductionmentioning

confidence: 99%

Preparation and In Vitro/In Vivo Evaluation of Orally Disintegrating/Modified-Release Praziquantel Tablets

Wen

Deng

et al. 2021

Pharmaceutics

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This study was designed to develop orally disintegrating/sustained-release praziquantel (PZQ) tablets using the hot-melt extrusion (HME) technique and direct compression, and subsequently evaluate their release in in vitro and in vivo pharmacokinetics. For the extrusion process, hypromellose acetate succinate (HPMCAS)-LG was the carrier of pure PZQ, with a standard screw configuration used at an extrusion temperature of 140 °C and a screw rotation speed of 100 rpm. Differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X-ray diffraction (PXRD) and Fourier-transform infrared spectroscopy (FTIR) were performed to characterize the extrudate. Orally disintegrating/sustained-release praziquantel tablets (PZQ ODSRTs) were prepared by direct compression after appropriate excipients were blended with the extrudate. The release amount was 5.10% in pH 1.0 hydrochloric acid at 2 h and over 90% in phosphoric acid buffer at 45 min, indicating the enteric-coating character of PZQ ODSRTs. Compared with the pharmacokinetics of marketed PZQ tablets (Aipuruike®) in dogs, the times to peak (Tmax), elimination half-life (t1/2λ) and mean residence time (MRT) were extended in PZQ ODSRTs, and the relative bioavailability of PZQ ODSRTs was up to 184.48% of that of Aipuruike®. This study suggested that PZQ ODSRTs may have potential for the clinical treatment of parasitosis.

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Polymorphic Transformation of Indomethacin during Hot Melt Extrusion Granulation: Process and Dissolution Control

Cited by 20 publications

References 22 publications

Formulation Development of Mucoadhesive Microparticle-Laden Gels for Oral Mucositis: An In Vitro and In Vivo Study

Formulation Development of Mucoadhesive Microparticle-Laden Gels for Oral Mucositis: An In Vitro and In Vivo Study

Stabilization of Metastable Indomethacin α in Cellulose Nanocrystal Aerogel Scaffolds

Preparation and In Vitro/In Vivo Evaluation of Orally Disintegrating/Modified-Release Praziquantel Tablets

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