The effect of excipients on the stability of levothyroxine sodium pentahydrate tablets

Patel, Himanshu; Stalcup, Apryll M.; Dansereau, Richard J.; Sakr, Adel

doi:10.1016/s0378-5173(03)00387-9

Cited by 48 publications

(54 citation statements)

References 9 publications

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“…As isotonic agents, cationic-CMs are naturally hydrophilic and can thereby freely disperse in water, resulting in solutions with an osmotic pressure similar to that of body uid. [70][71][72] (c) Enhanced pharmaceutical formulations. Studies concerning the direct hybridization of clay minerals and drugs are rapidly increasing due to the superior characteristics of clay minerals necessary for improving the formulation of pharmaceutical products.…”

Section: Cationic-cm In Pharmaceutical Productsmentioning

confidence: 99%

Biomedical applications of cationic clay minerals

2015

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Clay minerals have been a subject of interest owing to their ready availability in nature, a wide range of applications in various industries, and particularly their current and potential biomedical applications.They have been widely used for curative and protective purposes by humans since ancient times.Cationic clay minerals possess specific physicochemical characteristics such as high surface reactivity (high adsorption, cation exchange, colloidal or swelling capacity), good rheological behavior, high acidabsorbing capacity, and high dispersibility in water, which renders them suitable for various biomedical applications. Only a few reviews have exclusively discussed the biomedical applications of clay minerals, and to our knowledge, there is no updated review focusing on cationic clay minerals and their applications in pharmaceuticals, cosmetics, and regenerative medicine. In this review, we provide a brief introduction on natural, synthetic, and hybrid cationic clay minerals followed by a detailed discussion about their applications in biological systems.

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Section: Cationic-cm In Pharmaceutical Productsmentioning

confidence: 99%

Biomedical applications of cationic clay minerals

2015

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“…Critical dose drugs are defined as the drugs in which comparatively small differences in dose or concentration may lead to serious therapeutic failures and/or serious adverse drug reactions. Levothyroxine has a complex stability profile and is sensitive to light, temperature, moisture, pH, and oxidation (17)(18)(19)(20)(21)(22). Tablets split in advance and returned into the bottle may be subject to stability problems: increased friability and fragmentation, hygroscopic adsorption of water, and altered shelf-life due to, for example, a break in the tablet's protective coating (12).…”

Section: Introductionmentioning

confidence: 99%

Tablet Splitting of a Narrow Therapeutic Index Drug: A Case with Levothyroxine Sodium

et al. 2010

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Abstract. Levothyroxine is a narrow therapeutic index, and to avoid adverse effect associated with under or excessive dosage, the dose response is carefully titrated. The tablets are marketed with a score providing an option to split. However, there are no systematic studies evaluating the effect of splitting on dose accuracy, and current study was undertaken to evaluate effects of splitting and potential causes for uniformity failures by measuring assay and content uniformity in whole and split tablets. Stability was evaluated by assaying drug for a period of 8 weeks. Effect of formulation factors on splittability was evaluated by a systematic investigation of formulation factors by preparing levothyroxine tablets in house by varying the type of excipients (binder, diluent, disintegrant, glidant) or by varying the processing factors (granulating liquid, mixing type, compression pressure). The tablets were analyzed using novel analytical tool such as near infrared chemical imaging to visualize the distribution of levothyroxine. Assay was not significantly different for whole versus split tablets irrespective of method of splitting (hand or splitter), and splitting also had no measurable impact on the stability. Split tablets either by hand or splitter showed higher rate of content uniformity failures as compared to whole tablets. Tablet splitter produced more fragmentation and, hence, more content uniformity and friability failures. Chemical imaging data revealed that the distribution of levothyroxine was heterogeneous and was dependent on type of binder and the process used in the manufacture of tablets. Splitting such tablets could prove detrimental if sub-or super-potency becomes an issue.

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“…Instability and inconsistency in L-T 4 tablet potency over time and between lots have also been ongoing FDA concerns (7,(17)(18)(19)(20), with multiple product recalls due to inconsistent potency and instability (18,(21)(22)(23)(24). These issues exacerbate bioequivalence concerns, as bioequivalence testing depends on the presumption that brands are at least intrabrand bioequivalent before testing them for bioequivalence against each other.…”

Section: Introductionmentioning

confidence: 99%

TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T₄Bioequivalence

Eisenberg¹,

DiStefano²

2009

Thyroid

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Background: FDA Guidance for pharmacokinetic (PK) testing of levothyroxine (L-T 4 ) for interbrand bioequivalence has evolved recently. Concerns remain about efficacy and safety of the current protocol, based on PK analysis following supraphysiological L-T 4 dosing in euthyroid volunteers, and recent recalls due to intrabrand manufacturing problems also suggest need for further refinement. We examine these interrelated issues quantitatively, using simulated what-if scenarios testing efficacy of a TSH-based protocol and tablet stability and absorption, to enhance precision of L-T 4 bioequivalence methods. Methods: We use an updated simulation model of human thyroid hormone regulation quantified and validated from data that span a wide range of normal and abnormal thyroid system function. Bioequivalence: We explored a TSH-based protocol, using normal replacement dosing in simulated thyroidectomized patients, switching brands after 8 weeks of full replacement dosing. We simulated effects of tablet potency differences and intestinal absorption differences on predicted plasma TSH, T 4 , and triiodothyronine (T 3 ) dynamics. Stability: We simulated effects of potency decay and lot-by-lot differences in realistic scenarios, using actual tablet potency data spanning 2 years, comparing the recently reduced 95-105% FDA-approved potency range with the original 90-110% range. Results: A simulated decrease as small as 10-15% in L-T 4 or its absorption generated TSH concentrations outside the bioequivalence target range (0.5-2.5 mU=L TSH), whereas T 3 and T 4 plasma levels were maintained normal. For a 25% reduction, steady-state TSH changed 300% (from 1.5 to 6 mU=L) compared with <25% for both T 4 and T 3 (both within their reference ranges). Stability: TSH, T 4 , and T 3 remained within normal ranges for most potency decay scenarios, but tablets of the same dose strength and brand were not bioequivalent between lots and between fresh and near-expired tablets. Conclusions: A pharmacodynamic TSH-measurement bioequivalence protocol, using normal L-T 4 replacement dosing in athyreotic volunteers, is likely to be more sensitive and safer than current FDA Guidance based on T 4 PK. The tightened 95-105% allowable potency range for L-T 4 tablets is a significant improvement, but otherwise acceptable potency differences (whether due to potency decay or lot-by-lot inconsistencies) may be problematic for some patients, for example, those undergoing high-dose L-T 4 therapy for cancer.

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The effect of excipients on the stability of levothyroxine sodium pentahydrate tablets

Cited by 48 publications

References 9 publications

Biomedical applications of cationic clay minerals

Biomedical applications of cationic clay minerals

Tablet Splitting of a Narrow Therapeutic Index Drug: A Case with Levothyroxine Sodium

TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T₄Bioequivalence

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The effect of excipients on the stability of levothyroxine sodium pentahydrate tablets

Cited by 48 publications

References 9 publications

Biomedical applications of cationic clay minerals

Biomedical applications of cationic clay minerals

Tablet Splitting of a Narrow Therapeutic Index Drug: A Case with Levothyroxine Sodium

TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T4Bioequivalence

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Product

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TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T₄Bioequivalence