Decrease in the Rate of Capsule Dissolution Due to Formaldehyde from Polysorbate 80 Autoxidation

Chafetz, Lester; Hong, Wen-Hai; Tsilifonis, Dimitri C.; Taylor, Anne K.; Philip, Jose

doi:10.1002/jps.2600730846

Cited by 41 publications

(22 citation statements)

References 4 publications

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“…It is a common phenomenon for hard gelatin capsules to show a decrease in dissolution rates when stored at 408C/75% RH. 24 This phenomenon can be the main contributor to the decreased dissolution seen with the solid dispersion formulation, since only a few crystals were observed in the samples stored at 408C/75% RH for 16 months.…”

Section: Stabilitymentioning

confidence: 96%

Development of clinical dosage forms for a poorly water soluble drug I: Application of polyethylene glycol–polysorbate 80 solid dispersion carrier system

Dannenfelser

Joshi

et al. 2004

Journal of Pharmaceutical Sciences

114

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Section: Stabilitymentioning

confidence: 96%

Development of clinical dosage forms for a poorly water soluble drug I: Application of polyethylene glycol–polysorbate 80 solid dispersion carrier system

Dannenfelser

Joshi

et al. 2004

Journal of Pharmaceutical Sciences

114

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“…Their data show that capsules containing Polysorbate 80 showed film formation after 1 month at 37 °C/80% RH, and the dissolution was lower after storage at these conditions. The decrease in capsule dissolution was due to formaldehyde formation from Polysorbate 80 autooxidation (25). Likewise, in another study (26), nifedipine SGCs failed the dissolution test using the paddle as a result of pellicle formation upon storage for 208 days at 25 °C/60% RH and 40 °C/75% RH.…”

Section: Stability Studiesmentioning

confidence: 87%

“…Chafetz et al (25) reported that a considerable decrease in the dissolution rate of the drug gemifibrozil was observed from SGC capsule formulations that were stored at 37 and 45 °C/80% RH for up to a 3-month period (25). Their data show that capsules containing Polysorbate 80 showed film formation after 1 month at 37 °C/80% RH, and the dissolution was lower after storage at these conditions.…”

Section: Stability Studiesmentioning

confidence: 99%

Development of a Discriminating Dissolution Method for Immediate-Release Soft Gelatin Capsules Containing a BCS Class II Compound

Damian¹,

Harati²,

Pathak³

et al. 2016

Dissolution Technol.

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The purpose of this study was to develop a robust dissolution procedure for liquid-filled, soft gelatin capsules (SGCs) that can distinguish small but real changes in drug product formulation. SGCs were manufactured using different ratios of fill formulations. The formulations were evaluated by performing dissolution testing on fresh capsules and capsules that were aged at different time points and conditions. USP Apparatus 1 (basket) and 2 (paddle) at rotating speeds of 50, 75, or 100 rpm were used to evaluate the release characteristics of the formulations. The model-independent method using difference factor (f1) and similarity factor (f2) was employed to compare dissolution profiles. Dissolution data showed that fill material characteristics played a major role in controlling the rate of dissolution of our drug products. The basket increased the discriminatory power of the dissolution process regardless of speed. We observed that the paddle rotation speed may impact discrimination power but not the ability of the method to discriminate. The basket was successful for the quality assessment and characterization of formulation changes of our drug products. Through understanding of drug product characteristics and evaluating parameters of dissolution testing, a methodology can be established to enable batch-to-batch evaluation.

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“…However, before USP <1094> was published, gelatin capsule cross-linking phenomena, linked to decreased drug release, were described in several different ways (Table 1). The most frequent observation is a significant increase in disintegration time (8,11,38,40,41). The other observations are the formation of a gellike film (11,14,31,40), swollen, rubbery elastic matrix (8,14,22), or gelling with embedded drug blend (41).…”

Section: Visual Observationmentioning

confidence: 99%

“…The most frequent observation is a significant increase in disintegration time (8,11,38,40,41). The other observations are the formation of a gellike film (11,14,31,40), swollen, rubbery elastic matrix (8,14,22), or gelling with embedded drug blend (41). The differences in the reported descriptions might be due to the different experiences of the analysts who performed the dissolution testing.…”

Section: Visual Observationmentioning

confidence: 99%

Dissolution of Gelatin Capsules: Evidence and Confirmation of Cross-Linking

Lu¹,

Shah²

2017

Dissolution Technol.

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Cross-linking is a common problem in the dissolution of gelatin capsules. Cross-linking is characterized by a bridge across the peptide backbone of the gelatin molecule which creates water insoluble membranes or pellicles during dissolution testing. The chemical covalent bonding between gelatin chains is typically triggered by catalytic amounts of aldehyde and/or from exposure to high temperature and humidity. Cross-linking gelatin capsules results in a slower release of the drug or no release at all in common dissolution media. If the gelatin capsule dissolution fails acceptance criteria due to evidence of cross-linking, the US Pharmacopeia allows the use of enzymes in the dissolution medium and requires twotier dissolution testing. Studies have shown that drugs from cross-linked capsules are available in vivo to the patient, justifying the use of enzymes in the in vitro dissolution test. The literature contains several examples supporting evidence of cross-linking. However, confirming the degree of cross-linking continues to be a practical challenge due to a lack of quantitative procedures for measuring the extent of cross-linking and variability in options for formulations, excipients, level and types of stresses, and the experience level of the analysts. This article reviews the methodologies to confirm the evidence of cross-linking such as visual observation, capsule shell switch test, and spectroscopic determination of cross-linking, with an aim to facilitate the discussion and establishment of an acceptable standard approach.

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Decrease in the Rate of Capsule Dissolution Due to Formaldehyde from Polysorbate 80 Autoxidation

Cited by 41 publications

References 4 publications

Development of clinical dosage forms for a poorly water soluble drug I: Application of polyethylene glycol–polysorbate 80 solid dispersion carrier system

Development of clinical dosage forms for a poorly water soluble drug I: Application of polyethylene glycol–polysorbate 80 solid dispersion carrier system

Development of a Discriminating Dissolution Method for Immediate-Release Soft Gelatin Capsules Containing a BCS Class II Compound

Dissolution of Gelatin Capsules: Evidence and Confirmation of Cross-Linking

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