Accelerated stability modeling of recrystallization from amorphous solid Dispersions: A Griseofulvin/HPMC-AS case study.

Amorphous solid dispersions (ASDs) represent an important approach for enhancing oral bioavailability for poorly water soluble compounds; however, assuring that these ASDs do not recrystallize to a significant extent during storage can be time-consuming. Therefore, various efforts have been undertaken to predict ASD crystallization levels with kinetic models. However, only limited success has been achieved due to limits on crystal content quantification methods and the complexity of crystallization kinetics.

Accelerated shelf life modeling of appearance change in drug products using ASAP.

An accelerated stability model approach was demonstrated to accurately predict the long-term shelf life of example drug substances and drug products (indigo carmine tablets and L-ascorbic acid powder) where appearance changes were shelf life-limiting. The products were exposed outside of packaging to conditions from 50 to 90 °C and 0-80% relative humidity for up to one month to accelerate appearance changes. The appearance changes of stressed samples were quantitated using the CIELAB color scale (calculated Δ*), where a visual assessment of appearance changes likely to be noticeable was used to assign a Δ* specification limit.

Stability screening of pharmaceutical cocrystals.

An efficient protocol for assessing both the chemical and physical stability of cocrystalline forms of active pharmaceutical ingredients (APIs) is proposed. In this protocol, the cocrystalline material is used to prepare two standard formulations, mimicking wet granulations, to make low-dose tablets. After designed stress testing at a range of temperatures and RH conditions, degradant formation is modeled from the data using ASAP to determine if the tablets have a minimum of a one-year shelf-life (25 °C/60% RH open).

Accelerated Stability Modeling for Peptides: a Case Study with Bacitracin.

The Accelerated Stability Assessment Program (ASAP) was applied for the first time to a peptide, the antibiotic active pharmaceutical ingredient bacitracin. Bacitracin and its complex with zinc were exposed to temperature and relative humidity conditions from 50 to 80°C and from 0 to 63% for up to 21 days. High-performance liquid chromatography was used to analyze the stressed samples for both degradant formation and loss of the active (bacitracin A) and two inactive isoforms, with identities confirmed by mass spectrometry.

Modeling of in-use stability for tablets and powders in bottles.

A model is presented for determining the time when an active pharmaceutical ingredient in tablets/powders will remain within its specification limits during an in-use period; that is, when a heat-induction sealed bottle is opened for fixed time periods and where tablets are removed at fixed time points. This model combines the Accelerated Stability Assessment Program to determine the impact on degradation rates of relative humidity (RH) with calculations of the RH as a function of time for the dosage forms under in-use conditions. These calculations, in a conservative approach, assume that the air inside bottles with broached heat-induction seals completely exchanges with the external environment during periods when the bottle remains open.

A scientific and statistical analysis of accelerated aging for pharmaceuticals. Part 1: accuracy of fitting methods.

Three competing mathematical fitting models (a point-by-point estimation method, a linear fit method, and an isoconversion method) of chemical stability (related substance growth) when using high temperature data to predict room temperature shelf-life were employed in a detailed comparison. In each case, complex degradant formation behavior was analyzed by both exponential and linear forms of the Arrhenius equation. A hypothetical reaction was used where a drug (A) degrades to a primary degradant (B), which in turn degrades to a secondary degradation product (C).

Impact of sertraline salt form on the oxidative stability in powder blends.

Oxidation of active pharmaceutical ingredients is a common chemical degradation process occurring in solid dosage forms. The aim of this study was to investigate the tendency of various sertraline salts to oxidize in powder blends containing a basic additive. A different extent of conversion of each salt to the free base was observed to occur in the presence of the basic additive, consistent with their respective pHmax values.

A generalized relation for solid-state drug stability as a function of excipient dilution: temperature-independent behavior.

A proposed generalized relationship for the impact of excipients on the solid-state chemical stability of drug products is presented and shown to be consistent across multiple degradation products with two example drugs. In this model, when the number of drug particles is comparable to the number of excipient particles, the impact of the excipient on the degradant formation rate is independent of drug concentration. In contrast, when the number of drug particles is in excess of the number of excipient particles, a power-law relation (linear correlation between the logarithm of the degradant formation rate and the logarithm of the reciprocal of the drug concentration) is proposed based on a "quasi-liquid" model where drug particles fill in interstices between excipients.

Relative humidity hysteresis in solid-state chemical reactivity: a pharmaceutical case study.

The chemical reaction rate for solid-state product formation in a pharmaceutical case study was monitored by equilibration with either a 75%, 21.5%, 75% relative humidity (RH) cycle ("high-low-high", HLH) or a 21.5%, 75%, 21.

The application of the Accelerated Stability Assessment Program (ASAP) to quality by design (QbD) for drug product stability.

An isoconversion paradigm, where times in different temperature and humidity-controlled stability chambers are set to provide a fixed degradant level, is shown to compensate for the complex, non-single order kinetics of solid drug products. A humidity-corrected Arrhenius equation provides reliable estimates for temperature and relative humidity effects on degradation rates. A statistical protocol is employed to determine best fits for chemical stability data, which in turn allows for accurate estimations of shelf life (with appropriate confidence intervals) at any storage condition including inside packaging (based on the moisture vapor transmission rate of the packaging and moisture sorption isotherms of the internal components).

Osmotic capsules: A universal oral, controlled-release drug delivery dosage form.

An osmotic, oral, controlled-release capsule is described. This capsule provides drug delivery at fixed delivery rates (T(80%)=6 or 14h) independent of drug properties (e.g.

Package selection for moisture protection for solid, oral drug products.

This review describes how best to select the appropriate packaging options for solid, oral drug products based on both chemical and physical stability, with respect to moisture protection. This process combines an accounting for the initial moisture content of dosage form components, moisture transfer into (out of) packaging based on a moisture vapor transfer rate (MVTR), and equilibration between drug products and desiccants based on their moisture sorption isotherms to provide an estimate of the instantaneous relative humidity (RH) within the packaging. This time-based RH is calculationally combined with a moisture-sensitive Arrhenius equation (determined using the accelerated stability assessment program, ASAP) to predict the drug product's chemical stability over time as a function of storage conditions and packaging options.

Use of scoring to induce reproducible drug delivery from osmotic pulsatile tablets.

An osmotic-controlled pulsatile delivery technology was developed for targeted drug delivery. This novel system consists of a tablet core surrounded by an osmotic coating that has been mechanically compromised in strategic locations to facilitate reliable drug release at a given time point after administration. The tablet core contains a high drug load in addition to several osmotic agents and swellable polymers, and the surrounding mechanically-compromised osmotic coating consists of a semipermeable membrane that has been scored with a razor blade in several key locations.

Extrudable core system: development of a single-layer osmotic controlled-release tablet.

A new controlled-release, extrudable core system (ECS) tablet has been developed which osmotically delivers high doses of low solubility active pharmaceutical ingredients (API's). The tablet has a single core formed in a modified oval shape with a semi-permeable coating. The core contains hydroxyethylcellulose, which serves to entrain the API particles as they are extruded out a hole in the coating at one end of the tablet, and a sugar, which provides the osmotic driving force for water imbibing.

N-methylation and N-formylation of a secondary amine drug (varenicline) in an osmotic tablet.

Significant degradation of the amine-based smoking cessation drug varenicline tartrate in an early development phase osmotic, controlled-release (CR) formulation yields predominantly two products: N-methylvarenicline (NMV) and N-formylvarenicline (NFV). NMV is produced by reaction of the amine moiety with both formaldehyde and formic acid in an Eschweiler-Clarke reaction, while NFV is formed by reaction of formic acid alone with varenicline. This represents the first report of these reactions occurring on storage of solid pharmaceutical formulations.

A critical review of gastric retentive controlled drug delivery.

The promise of gastric retentive drug delivery systems has propagated numerous investigations and the formation of a number of companies. Three technologies have involved a substantial number of human clinical trials: mucoadhesion, density modification, and expansion. Standard, nondisintegrating controlled-release tablets can display significant gastric retention times, with that retention time being proportional to the calorie intake.

Improved protocol and data analysis for accelerated shelf-life estimation of solid dosage forms.

Purpose: To propose and test a new accelerated aging protocol for solid-state, small molecule pharmaceuticals which provides faster predictions for drug substance and drug product shelf-life.

Materials And Methods: The concept of an isoconversion paradigm, where times in different temperature and humidity-controlled stability chambers are set to provide a critical degradant level, is introduced for solid-state pharmaceuticals. Reliable estimates for temperature and relative humidity effects are handled using a humidity-corrected Arrhenius equation, where temperature and relative humidity are assumed to be orthogonal.

Reactions of aliphatic thiyl radicals in the solid state: photoisomerization of trans-4,5-dihydroxy-1,2-dithiacyclohexane and oxidation of dithiothreitol.

A description of free-radical reactions in the solid state is important for some processes causing long-term stability problems of natural and synthetic products. Recent studies revealed that, in the solid state, mercaptooctadecanethiyl radicals, C(18)H(37)S., do not abstract a hydrogen atom from mercaptooctadecane, C(18)H(37)SH, but yield perthiyl radicals, C(18)H(37)SS.

Purification of pharmaceutical excipients with supercritical fluid extraction.

Supercritical fluid extraction (SFE), with carbon dioxide as the solvent, was tested for its ability to remove common reactive impurities from several pharmaceutical excipient powders including starch, microcrystalline cellulose (MCC), hydroxypropylcellulose (HPC), polyethylene oxide (PEO), and polyvinylpyrrolidone (PVP). Extraction of the small molecule impurities, formic acid and formaldehyde, was conducted using SFE methods under conditions that did not result in visible physical changes to polymeric excipient powders. It could be shown that spiked, largely surface-bound, impurities could be removed effectively; however, SFE could only remove embedded impurities in the excipient particles after significant exposure times due to slow diffusion of the impurities to the particle surfaces.

Accelerated aging: prediction of chemical stability of pharmaceuticals.

Methods of rapidly and accurately assessing the chemical stability of pharmaceutical dosage forms are reviewed with respect to the major degradation mechanisms generally observed in pharmaceutical development. Methods are discussed, with the appropriate caveats, for accelerated aging of liquid and solid dosage forms, including small and large molecule active pharmaceutical ingredients. In particular, this review covers general thermal methods, as well as accelerated aging methods appropriate to oxidation, hydrolysis, reaction with reactive excipient impurities, photolysis and protein denaturation.

Press-coating of immediate release powders onto coated controlled release tablets with adhesives.

A novel adhesive coating was developed that allows even small quantities of immediate-release (IR) powders to be press-coated onto controlled-release (CR), coated dosage forms without damaging the CR coating. The process was exemplified using a pseudoephedrine osmotic tablet (asymmetric membrane technology, AMT) where a powder weighing less than 25% of the core was pressed onto the osmotic tablet providing a final combination tablet with low friability. The dosage form with the adhesive plus the press-coated powder showed comparable sustained drug release rates to the untreated dosage form after an initial 2-h lag.

A computational model for particle size influence on drug absorption during controlled-release colonic delivery.

The effect of particle size on the percent drug absorbed is computationally modeled for controlled-release dosage forms that deliver drug particles to the colon. The relative benefit of reducing particle size is mapped on a diagram of the drug's absorption rate constant (estimated from rat intestinal perfusion, CACO-2 or human intubation permeation rates) versus the drug's solubility. Some drugs fall into a limit of high percentage absorption even with large particles such that particle size reduction has little impact.

Use of oxygen scavengers to stabilize solid pharmaceutical dosage forms: a case study.

A case study is described where degradation of a solid pharmaceutical dosage form susceptible to oxidation is minimized by incorporation of an oxygen scavenger as part of the packaging. Extremely low oxygen levels are attainable within 24 hr of packaging, even with permeable high-density polyethylene bottles commonly used in the pharmaceutical industry. This packaging methodology allows for a practical formulation-independent pathway for reducing or eliminating oxidative instability.

Hydrolysis in pharmaceutical formulations.

This literature review presents hydrolysis of active pharmaceutical ingredients as well as the effects on dosage form stability due to hydrolysis of excipients. Mechanisms and measurement methods are discussed and recommendations for formulation stabilization are listed.

Stabilization of pharmaceuticals to oxidative degradation.

A guide for stabilization of pharmaceuticals to oxidation is presented. Literature is presented with an attempt to be a ready source for data and recommendations for formulators. Liquid and solid dosage forms are discussed with options including formulation changes, additives, and packaging documented.