Stability studies are an integral part of the drug development process for any drug product. In addition to monitoring chemical degradation, the physical stability of a drug product must also be evaluated to ensure that the drug release and performance is not affected by storage. In this study, directly compressed tablets of 16 different formulations were exposed to an accelerated stability program to quantify changes in tablet breaking force, porosity, contact angle and disintegration time. Tablets were exposed to five different storage conditions from 37∘C/30% relative humidity (RH) to 70∘C/75%RH with testing after 2 and 4 weeks of storage. Each formulation contained two different fillers (47% w/w each), a disintegrant (5% w/w) and magnesium stearate (1% w/w). The results show that tablets stored at high humidity show increases in porosity and decreases in tensile strength, particularly if they contain a highly hygroscopic filler such as microcrystalline cellulose (MCC). For tablets stored at high temperature, the most commonly affected property was the tablet wettability, measured by sessile drop contact angle measurements. These results are considered in combination with the performance-controlling disintegration mechanism (Maclean et al., 2021) to identify the critical properties which influence the performance after storage.

The disintegration process of pharmaceutical tablets is a crucial step in the oral delivery of a drug. Tablet disintegration does not only refer to the break up of the interparticle bonds, but also relates to the liquid absorption and swelling behaviour of the tablet. This study demonstrates the use of the sessile drop method coupled with image processing and models to analyse the surface liquid absorption and swelling kinetics of four filler combinations (microcrystalline cellulose (MCC)/mannitol, MCC/lactose, MCC/dibasic calcium phosphate anhydrous (DCPA) and DCPA/lactose) with croscarmellose sodium as a disintegrant. Changes in the disintegration performance of these formulations were analysed by quantifying the effect of compression pressure and storage condition on characteristic liquid absorption and swelling parameters. The results indicate that the disintegration performance of the MCC/mannitol and MCC/lactose formulations are driven by the liquid absorption behaviour. For the MCC/DCPA formulation, both liquid absorption and swelling characteristics affect the disintegration time, whereas DCPA/lactose tablets is primarily controlled by swelling characteristics of the various excipients. The approach discussed in this study enables a rapid (<1 min) assessment of characteristic properties that are related to tablet disintegration to inform the design of the formulation, process settings and storage conditions.

The design and manufacture of tablets is a challenging process due to the complex interrelationships between raw material properties, the manufacturing settings and the tablet properties. An important factor in formulation and process design is the fact that raw material and tablet properties drive the disintegration and dissolution performance of the final drug product. This study aimed to identify the mechanisms which control tablet disintegration for 16 different immediate-release placebo formulations based on raw material and tablet properties. Each formulation consisted of two fillers (47% each), one disintegrant and a lubricant. Tablets were manufactured by direct compression using four different combinations of the fillers microcrystalline cellulose (MCC), mannitol, lactose and dibasic calcium phosphate anhydrous (DCPA). The disintegration mechanism was primarily driven by the filler combination, where MCC/lactose tablets were identified as wettability controlled, MCC/mannitol tablets as dissolution controlled and DCPA-based tablets (MCC/DCPA and lactose/DCPA) as swelling controlled. A change of 2% in porosity for the wettability controlled tablets (MCC/lactose) caused a significant acceleration of the disintegration process (77% reduction of disintegration time), whereas for swelling controlled tablets (MCC/DCPA) the same porosity change did not considerably impact the disintegration process (3% change in disintegration time). By classifying these formulations, critical formulation and manufacturing properties can be identified to allow tablet performance to be optimised.

Risk-Based Predictive Stability (RBPS) tools, such as the Accelerated Stability Assessment Program (ASAP) and other models, are used routinely within pharmaceutical development to quickly assess stability characteristics, especially to understand mechanisms of degradation. These modeling tools provide stability insights within weeks that could take months or years to understand using long-term stability conditions only. Despite their usefulness, the knowledge gained through these tools are not as broadly used to support regulatory filing strategies. This paper aims to communicate how industry has used RBPS data to support regulatory submissions and discuss the regulatory feedback that was received.

OBJECTIVE:The aim of this study is to demonstrate the applicability of predictive stability studies to the degradation of drug substances.SIGNIFICANCE:The use of predicted stability studies during pharmaceutical development and in regulatory submissions is increasing, particularly in early phase to support an initial retest period/shelf life claim in the absence of standard stability data. These studies offer an alternative to standard stability testing and can facilitate clinical trials to be started earlier and medicines to reach patients faster. They involve a short-term stressed stability study, typically designed to degrade a drug substance or product to the specification level of the shelf life limiting attribute. The results are used to predict degradation under long-term storage conditions and enable stability understanding to be gained over a short time frame, using limited amounts of material.METHODS:In this work, Accelerated Stability Assessment Program (ASAP) studies were performed for 10 different drug substances and the predictions obtained for chemical degradation were compared to ICH compliant stability data.RESULTS:Across the studies good agreement was achieved, with the initial retest period predictions from the ASAP studies being conservative by design. When minimal degradation was observed during an ASAP study, it was demonstrated that at least a 12-month initial retest period could be supported.CONCLUSION:This comparison of ASAP predictions and ICH compliant stability data has demonstrated the ability of well-designed ASAP studies to predict the long-term chemical stability of drug substances.

Predictive stability studies allow the long-term stability characteristics of a drug substance or drug product to be characterized from extrapolation of results from a short-term stressed stability study. These studies are typically one month in duration and focus on chemical degradation. This chapter focuses on accelerated stability assessment program (ASAP) studies as one method of predicting stability. The main phases of performing an ASAP study are described including designing the protocol, setting down the studies, storing and analyzing the samples followed by reviewing and modeling the data and performing predictions. The applications of predictive stability studies are also discussed including in regulatory submissions.

Objective: The purpose of this study was to determine if electron paramagnetic resonance (EPR) spectroscopy could be used to develop a quick method to predict the longer-term photostability characteristics of active pharmaceutical ingredients (APIs) for use in the early development phase.Materials and methods: EPR spectroscopy was used to study the photodegradation of nearly fifty different APIs in the solid state.Results: Free radical formation was detected in all but three of the APIs studied and singlet oxygen formation was also detected in the presence of five of the APIs tested. The extent of free radical formation in each API after 10 minutes exposed to light was used to rank the APIs in terms of their stability characteristics and determine the probable risk of photodegradation of the API during International Conference on Harmonisation (ICH) compliant photostability testing. A correlation was obtained between the extent of free radical formation on exposure to light and the known level of photodegradation products formed during ICH compliant testing.Conclusion: The EPR methods were shown to have the potential to predict the ICH level of photodegradation for an API in the solid state using only a small amount of sample and after just 10 minutes exposed to light. This testing can be performed in a shorter time frame than ICH compliant testing and can potentially be used early in development to predict the photostability characteristics of an API.

The spin trapping ability of the nitrones 2,4-disulphophenyl-N-tert-butyl nitrone (NXY-059), 2-sulphophenyl-N-tert-butyl nitrone (S-PBN) and alpha-phenyl-N-tert-butyl nitrone (PBN) for both hydroxyl and methanol radicals was investigated using electron paramagnetic resonance (EPR) spectroscopy. The radicals of interest were generated in situ in the spectrometer under constant flow conditions in the presence of each nitrone. The spin adducts formed were detected by EPR spectroscopy. This approach allowed for quantitative comparison of the EPR spectra of the spin adducts of each nitrone. The results obtained showed that NXY-059 trapped a greater number of hydroxyl and methanol radicals than the other two nitrones, under the conditions studied.

Related to improving persistence assessment of active pharmaceutical ingredients (APIs), direct aqueous photolysis of beta-blockers: propranolol (hydrochloride salt), atenolol, and metoprolol (succinate salt) were investigated by exposing the samples (0.0003-10 mg L(-1)) to a solar irradiator (filtered xenon lamp: 290-800 nm) at 20-26 degrees C. Results suggested that direct photolysis in optically dilute solutions followed pseudo first-order kinetics. The measured half-lives of propranolol, atenolol, and metoprolol were approximately 16, 350, and 630 h, respectively. These were 3-5 orders of magnitude slower than the estimated minimum half-lives. The measured half-lives were related to day light surface conditions by comparing the light intensity of the lamp and the sun at different latitudes and seasons. Major direct photolysis products were identified from propranolol that led to a proposed reaction pathway, involving ring oxidation, rearrangement, and deoxygenation. Electron paramagnetic resonance (EPR) spectroscopy results confirmed that at least one carbon-based radical intermediate was formed during the direct photolysis of propranolol in aqueous solutions. The overall results demonstrated that with fast direct photolysis half-lives, propranolol is unlikely to be persistent in natural waters. Further work is needed to investigate indirect photolysis of atenolol and metoprolol in surface waters in order to understand the overall persistence of these APIs in the environment.

The effects of lactide:glycolide ratio and γ-irradiation on the stability characteristics of poly(d,l-lactide-co-glycolide) (dl-PLG) co-polymer and microspheres were studied. Samples containing 50:50, 65:35, 75:25, 85:15 and 95:5 lactide:glycolide were studied as both the raw polymer and microspheres. The samples were characterised and degradation was monitored using a variety of spectroscopic, chromatographic, thermal and particle analysis techniques. The lactide:glycolide ratio was shown to be an important parameter in controlling the degradation of PLG co-polymer, especially in the microspheres, and the raw polymer samples were observed to be less stable than the microspheres. γ-Irradiation was shown to reduce the molecular weight of the PLG samples without significantly affecting the polydispersity, suggesting a random chain scission degradation mechanism. The detrimental effects of γ-irradiation were shown to continue on storage of the samples for 4 weeks in the solid state at ambient and accelerated conditions.

Gamma radiation of poly (lactide-co-glycolide) raw polymers and processed microspheres under vacuum and at 77 K results in the formation of a series of free radicals. The resulting powder electron paramagnetic resonance (EPR) spectrum contains a distribution of several different radicals, depending on the annealing temperature, and is therefore difficult to interpret. By utilising the selectivity of the electron nuclear DOuble resonance (ENDOR) and associated ENDOR induced EPR (EIE) techniques, a more direct approach for the deconvolution of the EPR spectrum can be achieved. Using this approach, the radiolytically induced CH3 *CHC(O)R- chain scission radical was identified at 120 K by simulation of the EIE spectrum. At elevated temperatures (250 K), this radical decays considerably and the more stable radicals -O*CHC(O)-, CH3 *C(OR)C(O)- and CH3 *C(OH)C(O)- predominate. This work demonstrates the utility of the EIE approach to supplement and aid the interpretation of powder EPR spectra of radicals in a polymer matrix.