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. To increase the prediction accuracy, the accelerated stability assessment program (ASAP), employing isoconversion (time to hit a specification limit) and a modified Arrhenius approach, are employed here for predictive shelf -life modeling. In the current study, a model ASD was prepared by spray drying griseofulvin and HPMC-AS-LF. This ASD was stressed under a designed combinations of temperature, relative humidity and time with the conditions set to ensure stressing was carried out below the glass transition temperature (T g ) of the ASD. Crystal content quantification method by Xray powder diffraction (XRPD) with sufficient sensitivity was developed and employed for stressed ASD. Crystallization modeling of the griseofulvin ASD using ASAP prime (R) demonstrated good agreement with long-term (40 degrees C/75 %RH) crystallinity levels and support the use of this type of accelerated stability studies for further improving ASD shelf -life prediction accuracy.

Purpose This work evaluates the probability and impact of using high-temperature accelerated aging for determining shelf life based on reaction mechanism changes. Method Simulations are made to calculate the probability of a significant error in determining shelf life based on high-temperature stability data. Published distributions of activation energies and varied transition temperatures ( T x , the temperature where both processes are equally involved) to calculate shelf impacts from mechanism changes using high temperature data to assign long-term shelf life. Results High-temperature mechanism changes with respect to individual degradation products rarely occur when using accelerated stability studies. Even in the uncommon scenario of a mechanism change with temperature, the probability of there being a practical error in a shelf life determination from using these data is calculated to be less than 25%. High temperature modeling does bring a prediction risk when there is either a phase change or secondary degradation. Conclusion High temperature data can reliably be used to determine long-term shelf life in most cases. Changes of mechanism with temperature rarely occur and when they do, most often they will not result in a longer shelf life assigned than will ultimately be observed.

Abstract 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 ΔE*), where a visual assessment of appearance changes likely to be noticeable was used to assign a ΔE* specification limit. ASAPprime ® software was employed to create an isoconversion paradigm, modeled in packaging by the moisture-modified Arrhenius equation, that predicted the color changes of the products within the error bars of the model to nine months at 25 °C/60% RH, 30 °C/65% RH, and 40 °C/75% RH. Overall, these case studies indicate that the ASAPprime ® approach for accelerated stability studies are a fast, accurate approach to modeling appearance changes.

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 ASAPprime(R) to determine if the tablets have a minimum of a one-year shelf-life (25 degrees C/60% RH open). When the cocrystals provide a kinetic solubility enhancement over the un-complexed API, a physical assessment of the cocrystal stability is carried out using the same tablets at selected stress conditions. For this assessment, kinetic solubility (where the amount of buffer used to dissolve the tablet is adjusted to completely dissolve the cocrystalline form but leave most of the un-complexed form out of solution) changes are used to indicate whether there is a significant risk for physical instability on long-term storage. This process was exemplified using model cocrystals of APIs.

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. The solid dosages are assumed to sorb water at estimable rates during these openings. When bottles are capped, the moisture vapor transmission rate can be estimated to determine the changing RH inside the bottles between opening events. The impact of silica gel desiccants can also be included in the modeling.

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. These data were then analyzed using a humidity-corrected Arrhenius equation and isoconversion approach to create a shelf-life predicting model for typical storage conditions. Model fitting was found to be good with low residuals in both temperature and relative humidity axes for all parameters examined. The generated model’s predictions for both the native and zinc complex of bacitracin for both formation of the major degradation product (F) and loss of the active isoform (A) were consistent with longer-term measured values at 30°C/53%RH and 40°C/75%RH, validating this approach for accelerating the determination of long-term stability of a peptide.

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. Sertraline was found to undergo oxidation as the unioinized form, in both solution and powder blends that incorporated an oxidizing agent. In contrast, the ionized form of sertraline remained stable in both cases. Three sertraline salts undergoing a significant extent of conversion from salt to free form in the presence of tribasic sodium phosphate were found to oxidize extensively while sertraline benzoate which had a considerably lower extent of free base formation was more resistant to oxidation. The oxidative degradants were produced through oxidation at the amine functional group of sertraline which is where sertraline is ionized as the salt form. The link between oxidation tendency and the ionization state of sertraline in powder mixtures has thus been demonstrated in this study.

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). Calculated data with the fitting models were compared with the projected room-temperature shelf-lives of B and C, using one to four time points (in addition to the origin) for each of three accelerated temperatures. Isoconversion methods were found to provide more accurate estimates of shelf-life at ambient conditions. Of the methods for estimating isoconversion, bracketing the specification limit at each condition produced the best estimates and was considerably more accurate than when extrapolation was required. Good estimates of isoconversion produced similar shelf-life estimates fitting either linear or nonlinear forms of the Arrhenius equation, whereas poor isoconversion estimates favored one method or the other depending on which condition was most in error.

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. As predicted by this model, the experimental power-law lines have slopes of about 2/3 independent of temperature (0.61 ± 0.13 for n = 30 counting multiple degradation products and a range of temperatures and relative humidities for two drug products).

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). These methodologies provide both faster results and far better predictions of chemical stability limited shelf life (expiry) than previously possible. Precise shelf-life estimations are generally determined using a 2-week, product-specific protocol. Once the model for a product is developed, it can play a critical role in providing the product understanding necessary for a quality by design (QbD) filing for product approval and enable rational control strategies to assure product stability. Moreover, this Accelerated Stability Assessment Program (ASAP) enables the coupling of product attributes (e.g., moisture content, packaging options) to allow for flexibility in how control strategies are implemented to provide a balance of cost, speed, and other factors while maintaining adequate stability.

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., solubility) or drug loading, thereby allowing rapid development of investigational or commercial drugs, especially for proof-of-concept type clinical studies. The capsule body and cap are prepared with cellulose acetate and polyethylene glycol in acetone and water using high density polyethylene molds as templates and a conventional tablet pan coater. After the shells are removed from the molds manually, a laser hole is drilled in the end of the capsule body. The drug is introduced as a shaped tablet admixed with polyethylene oxide. A "push" tablet consisting of high molecular weight polyethylene oxide, microcrystalline cellulose, and sodium chloride is also inserted into the capsule body. The capsule halves lock together due to ridges, alleviating the need for a banding operation.

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%, 21.5% RH cycle ("low-high-low", LHL). For the HLH cycle, it was found that the degradant formation rate was reversible; that is, the rate at the final 75% RH step was equivalent to the rate at the initial 75% RH step. For samples equilibrated with the LHL cycle, a significantly higher rate of product formation was seen when the low RH condition was re-established than for the initial sample that had never been exposed to high RH. The observed hysteresis in degradant formation rate as a function of RH is not explained by hysteresis in the bulk moisture sorption isotherm, which is minimal in the case studied. It is suggested that high RH exposure impacts the solid-solid interface by either changing the amount of solid-solution present, by altering the mechanical properties of the material such that there is a greater mobility even when moisture is removed, or by altering the interfacial material to have a greater amount of moisture present even when dried.

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. While physical stability of dosage forms with respect to moisture has been less well documented, a process is recommended based on the threshold RH at which changes (e.g., dosage form dissolution, tablet hardness, drug form) become problematic. The overall process described allows packaging to be determined for a drug product scientifically, with the effect of any changes to storage conditions or packaging to be explicitly accounted for.

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. The components in the tablet core attract water into the core, causing it to swell and propagate the scores in the coating along the length of the tablet. After the scores have fully propagated, the coating bursts open, releasing the tablet core’s contents, including the drug, into the surrounding media. The variables that were investigated in this study included the configuration of the scores in the coating, the length of the scores, and the distance between the scores. The delivery system developed in this work is able to generate a reproducible dissolution profile consisting of a specific targeted lag time, between five minutes and two hours, followed by immediate release of the drug from the core. The performance of the system was validated in vitro using the drug salicylic acid. Unlike previously developed osmotic pulsatile delivery systems, the present system is able to accommodate higher drug loading levels, it is easier to manufacture, and has demonstrated more reproducible burst times (i.e. burst time) than several other pulsatile systems.

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. The dosage form has been successfully shown to control delivery of API over a range of delivery rates even with 50% of the tablet being API (up to about 500 mg).

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. Both formaldehyde and formic acid are formed from oxidative degradation of polyethylene glycol (PEG) used in an osmotic coating through a process heavily dependent on the physical state of the PEG. When the concentration of PEG in the coating is sufficiently low, the PEG remains phase compatible with the other component of the coating (cellulose acetate) such that its degradation (and the resulting drug reactivity) is effectively eliminated. Antioxidants in the coating and oxygen scavengers in the packaging also serve to prevent the PEG degradation, and consequently provide for drug stability.