Thermodynamic Stability and Degradation Kinetics of Thermolabile Longevity Compounds Under High-Shear Manufacturing Stress

Abstract

Thermolabile longevity-associated compounds and polyphenolic bioactives frequently experience coupled thermal, oxidative, pH, and mechanical stresses during manufacturing (e.g., high-shear mixing, high-pressure homogenization, and spray drying), which can accelerate chemical degradation and reduce delivered potency. Quantitative, process-relevant stability parameters are therefore required to define manufacturable design spaces and to guide protective formulation strategies.[1–3]

Methods in the present synthesis focus on quantitative evidence extracted from studies reporting (i) thermodynamic/thermal transitions by DSC/TGA (melting, decomposition onset, glass transitions, and staged mass-loss behavior) and (ii) degradation kinetics (pseudo-first-order/first-order models, Arrhenius activation energies, pH dependencies, and time-to-fraction-decomposed measures) for NAD⁺ precursors (NR/NRH/NMN), stilbenoids (resveratrol-related systems), flavonoids (quercetin, fisetin, rutin/esters), and curcuminoids.[4–11]

Results show that several representative longevity compounds have narrow thermal-processing windows in specific physical states. Nicotinamide riboside chloride (NRCl) exhibits an onset of melting at 120.7 ± 0.3 °C with rapid post-melt decomposition (e.g., 98% degradation at 130 °C by qNMR), while aqueous degradation follows pseudo-first-order kinetics with activation energies of 75.4–82.8 kJ·mol⁻¹ depending on pH.[4]

For trans-resveratrol, degradation kinetics are strongly pH- and temperature-dependent (e.g., half-life decreasing from 329 days at pH 1.2 to 3.3 minutes at pH 10), and accelerated-test extrapolation can be non-Arrhenius in tablet matrices.[7, 12]

High-shear unit operations can induce local heating and oxidative environments, as demonstrated by high-shear homogenization increasing outlet temperature with rotational speed and coinciding with 42.6% ascorbic-acid loss at 20,000 rpm, and by high-pressure homogenization mechanisms involving valve shear, cavitation, and turbulence at >100 MPa.[13, 14]

Conclusions emphasize integrating thermodynamic transition data (DSC/TGA/Tg) with kinetic models (Arrhenius, non-Arrhenius, and isoconversional methods) to produce time–temperature–shear maps and to rationally select mitigation strategies including encapsulation, amorphous solid dispersions, cyclodextrin/nanosponge systems, oxygen control, and shear/temperature minimization.[15–18]

Keywords: thermolabile bioactives; degradation kinetics; Arrhenius; DSC; TGA; high-pressure homogenization; spray drying; NAD⁺ precursors

1. Introduction

Longevity-relevant compounds are increasingly formulated as nutraceuticals, functional foods, and advanced delivery systems, motivating manufacturing routes that expose actives to combined stressors including heating, oxygen contact, water activity, pH excursions, and intense mechanical energy input.[3, 5, 14, 19]

For NAD⁺ precursor chemistries, aqueous and solid-state stability are central because reactivity can occur via hydrolysis of glycosidic or phosphate-linked motifs, and because processing temperatures can cross solid-state transition thresholds that precede rapid decomposition.[4, 6]

For polyphenols and related botanical actives, stability constraints include autoxidation, epimerization, and enzymatic oxidation to quinones, which are sensitive to temperature, pH, metal ions, and oxygen availability during processing.[17]

A practical implication is that manufacturing design cannot rely solely on nominal bulk temperature; instead, it must integrate (i) thermodynamic indicators such as glass transition, melting, and decomposition onset and (ii) kinetic models that capture the dependence of degradation on time, temperature, pH, oxygen, and (where measurable) mechanical energy input.[4, 9, 10, 14, 15]

This paper synthesizes quantitative evidence on representative longevity compounds and related bioactives for which the included sources provide explicit thermodynamic transitions and/or kinetic parameters, and it links those data to stress profiles of high-shear unit operations including high-shear mixing, high-pressure homogenization/microfluidization, mechanochemical milling, and spray drying.[1, 14, 15, 20]

2. Thermodynamic framework

Thermodynamic stability in manufacturing contexts is operationally assessed using measurable thermal events (DSC/TGA) and state descriptors (e.g., amorphous vs crystalline; glass transition temperature) that indicate when a compound or formulation transitions into states with higher molecular mobility and therefore higher reaction rates or different mechanisms.[4, 9, 15]

2.1 Gibbs free energy and phase stability

Several included sources explicitly compute Gibbs free energy changes for degradation processes or thermal destruction, providing a thermodynamic measure of feasibility under specific conditions.[8, 19]

For NR borate, degradation spontaneity was evaluated via a Gibbs free energy calculation, with (ΔG) reported as 2.43 kcal·mol⁻¹.[19]

For rutin and fatty-acid rutin esters under pyrolytic conditions, (ΔG) values were positive (84–245 kJ·mol⁻¹) alongside positive (ΔH) (60–242 kJ·mol⁻¹), indicating an endothermic and non-spontaneous pyrolysis profile in the reported analysis.[8]

In kinetic-formalism terms, several sources also apply transition-state and free-energy relations, such as using to interpret hydrolysis activation in a curcumin spiroborate complex system.[21]

2.2 Glass transition, melting, and decomposition onset

DSC and TGA provide complementary markers of process risk: melting or softening events can sharply increase diffusion and enable rapid chemical conversion, and TGA mass-loss onset can indicate the beginning of irreversible decomposition even in the apparent solid state.[4, 9, 15]

For NRCl, DSC indicates an onset of melting at 120.7 ± 0.3 °C and a melting peak at 125.2 ± 0.2 °C, followed by an immediate sharp exothermic event peaking at 130.8 ± 0.3 °C.[4]

Consistent with the DSC event sequence, qNMR quantification shows limited degradation at 115 °C (2%) but rapid loss at and above the melt region (7% at 120 °C; 55% at 125 °C; 98% at 130 °C; only 0.45% NR remaining at 140 °C).[4]

For NMN, one source reports that the compound decomposes rather than exhibiting a clear melting transition, with decomposition beginning at 160 °C and completing by 165 °C and an endothermic DSC peak at 162 °C with enthalpy of decomposition 184 kJ·mol⁻¹.[6]

For quercetin, combined DSC/TGA interpretation indicates that an intense DSC endotherm (maximum at 303 °C) is commonly misattributed to melting, while TGA indicates decomposition initiates at 230 °C and the endotherm overlaps with continuous mass loss; the reported "heat of fusion" for the 303 °C peak is 69–75 kJ·mol⁻¹.[9]

For fisetin, TGA shows a minor mass loss (~5%) attributed to evaporation of water from the crystalline sample and a major mass-loss event (~30.6%) at 369.6 °C attributed to decomposition of the molecule.[15]

For curcumin under inert nitrogen, one study reports that raw curcumin exhibits a complex decomposition process starting around 240 °C (5% mass loss) with a DTGA peak at 347 °C and 37% residue remaining at 600 °C (at 10 °C·min⁻¹).[18]

2.3 Amorphous and crystalline stability

Amorphous formulations may improve solubility and bioavailability but can alter thermal behavior and stability by increasing molecular mobility relative to crystalline forms, making glass transition temperature (Tg) a critical stability parameter.[15, 16]

Mechanochemically prepared fisetin amorphous solid dispersions (ASDs) show measurable Tg values in second heating scans and demonstrate compositional shifts in Tg consistent with miscibility: raw Eudragit® L100/EPO show Tg 147.1/55.4 °C, while fisetin ASDs show Tg values such as 144.2/71.8 °C and 145.9/76.7 °C depending on polymer and drug loading.[15]

For resveratrol and oxyresveratrol nanosponges, DSC shows that the melting endotherm of resveratrol (266.49 °C) disappears in the nanosponge formulations, which the authors attribute to encapsulation and possible amorphization of drug molecules within the nanosponge matrix.[16]

For quercetin, hydrogen bonding is proposed to both constrain melting-like softening and facilitate decomposition through bond weakening, and combined DSC/TGA interpretation concludes that quercetin does not simply melt but undergoes overlapping decomposition and structural relaxation/softening in the 150–350 °C range.[9]

3. Degradation kinetics models and parameters

Included sources use a range of kinetic models (first-order, pseudo-first-order, higher-order or sigmoidal forms) and temperature dependence treatments (Arrhenius and, in some cases, non-Arrhenius behavior), often motivated by pH dependence and complex multi-pathway degradation.[4, 7, 22]

3.1 Reaction-order models

A widely used baseline for solution-phase degradation is the integrated first-order model which appears in multiple included studies as a primary fit to concentration-time data under controlled pH and temperature.[4, 11, 12]

For NRCl in buffered aqueous solutions, degradation is described as pseudo-first-order, and this pseudo-first-order form is justified by buffer systems maintaining OH⁻/H₃O⁺ concentrations in great excess and approximately constant relative to NR concentration.[4, 23]

For fisetin and quercetin in phosphate buffer, the reported outcomes are presented as first-order degradation rate constants k (h⁻¹) that increase strongly with pH and temperature.[24]

For quercetin at 90 °C near neutral pH (6.5–7.5), a sigmoidal model was implemented and compared against a first-order model, with the sigmoidal model yielding k values 2.3–2.5× higher than first-order fits and a different half-life interpretation at pH 7.5.[22]

For spray-dried plant-extract markers, different apparent reaction orders were reported depending on excipient systems, including zero-order and second-order models for kaempferol (across excipient binaries) and a second-order model for quercetin across excipients.[20]

3.2 Arrhenius and Eyring treatments

Temperature dependence is frequently modeled by Arrhenius-type expressions, and multiple sources explicitly compute activation energies to parameterize shelf-life predictions and process thermal exposure.[4, 10, 12]

For NRCl degradation in aqueous solution, Arrhenius activation energies are reported as 75.4 (±2.9) kJ·mol⁻¹ at pH 2.0, 76.9 (±1.1) kJ·mol⁻¹ at pH 5.0, and 82.8 (±4.4) kJ·mol⁻¹ at pH 7.4.[4]

For trans-resveratrol at pH 7.4, Arrhenius analysis is reported as log(k_obs)=14.063−4425(1/T) (r = 0.97) with calculated activation energy 84.7 kJ·mol⁻¹.[12]

For curcumin in buffer/methanol mixture at pH 8.0, Arrhenius analysis between 37–60 °C yields (E_a)=79.6±2.2 kJ·mol⁻¹.[10]

For curcumin in GI-relevant aqueous media, Arrhenius plots show high linearity over 37–80 °C (r² values reported as 0.9967, 0.9994, 0.9886 for different media), with activation energies reported as 16.46, 12.32, and 9.75 kcal·mol⁻¹ for pH 7.4, pH 6.8, and 0.1 N HCl, respectively.[11]

Eyring analysis also appears in the hydrolytic decomposition study of a curcumin spiroborate ester (CBS), where an Eyring plot is reported to show a linear relationship with correlation 0.9988.[21]

3.3 Isoconversional and model-free methods

Several thermal-degradation studies apply isoconversional methods (e.g., KAS, FWO, Friedman) to compute conversion-dependent activation energies and thereby identify multi-step decomposition and mechanism changes.[8, 18, 25]

For rutin and rutin fatty-acid esters, activation energies vary substantially with conversion degree across 0.05 < (α) < 0.90, with reported ranges from 65 to 246 kJ·mol⁻¹; the authors interpret this as evidence that thermal degradation proceeds through a non-simple process with multiple stages.[8]

For resveratrol–β-cyclodextrin clathrates, activation energy increases with transformation degree, with reported increases from 110 to 130 kJ·mol⁻¹ (OFW method) and from 120 to 170 kJ·mol⁻¹ (Friedman method), which is interpreted as indicating a change in reaction mechanism as decomposition proceeds.[25]

For curcumin-loaded polymer systems under nitrogen, activation energies derived by multiple approaches (Kissinger, KAS, Friedman, and model-fitting) show broadly consistent magnitudes (e.g., 71 ± 5 kJ·mol⁻¹ by Kissinger; 77 ± 2 by KAS; 84 ± 3 by Friedman), and model selection indicates an F1 kinetic model with energies in the range 73–91 kJ·mol⁻¹.[18]

3.4 Coupled thermo-mechanical and oxidative degradation

High-shear manufacturing operations can couple mechanical energy dissipation to local heating and enhanced oxygen transfer, thereby amplifying oxidation-driven pathways in oxygen-sensitive bioactives.[13, 14, 17]

In high-shear homogenization of a beverage system, outlet temperature increases markedly with rotational speed (e.g., from 4.1 ± 0.7 °C at 0 rpm to 41 ± 1.2 °C at 20,000 rpm), and at the highest speed ascorbic acid is reduced by 42.6%, consistent with degradation being promoted by high temperature and oxidation.[13]

In high-pressure homogenization (HPH), the processing mechanism is explicitly attributed to shear stress distribution at the valve orifice, where fluid motion is disrupted, and to additional phenomena such as cavitation, turbulence, collision, and impingement, which together create intense mechanical and potentially oxidative stress.[14]

Oxidative coupling is also demonstrated in thermal oxidation experiments for quercetin: at 150 °C, quercetin degradation proceeds faster under oxygen than nitrogen (rate constants 0.868 h⁻¹ vs 0.253 h⁻¹) and is strongly accelerated when cholesterol and oxygen are present (rate constant 7.17 h⁻¹), consistent with radical-chain coupling between cholesterol hydroperoxide formation and quercetin degradation.[26]

For NRH, oxygen and temperature exert strong control: at 25 °C in DI water the reported degradation rate is 1.27×10⁻⁷ s⁻¹ under air (half-life 63 days) compared with 5.90×10⁻⁸ s⁻¹ under N₂ (half-life 136 days), and the authors state that NRH can be oxidized in the presence of oxygen and hydrolyzes quickly in acidic conditions.[5]

4. Compound-class review

The compound-focused synthesis below emphasizes quantified kinetic and thermodynamic parameters that can be directly used in manufacturing models, including activation energies, rate constants, half-lives, decomposition onsets, and glass-transition or melting-related constraints.[4, 11, 12, 15, 24]

4.1 NAD⁺ precursors

NAD⁺ precursor stability is strongly conditioned by hydrolysis susceptibility and by low tolerance to certain thermal transitions (particularly for NRCl in the melt region) and oxygen-driven oxidation (particularly for reduced forms like NRH).[4, 5]

NRCl shows pseudo-first-order degradation kinetics in aqueous solutions and exhibits activation energies that vary with pH (75.4–82.8 kJ·mol⁻¹), which quantitatively encodes both thermal sensitivity and pH dependence of the dominant hydrolysis pathway.[4]

A mechanistic basis is proposed as base-catalyzed hydrolysis in which NR decreases while nicotinamide (Nam) and sugar accumulate, and molar-balance evidence is presented indicating that for every NR molecule that degrades, one molecule of Nam and one of sugar are formed.[4]

In simulated GI fluids at physiological temperature and agitation (USP II paddle at 75 rpm and 37 °C), NRCl shows relatively limited short-term loss (e.g., ~97–99% remaining after 2 h in gastric media) but a measurable longer-term decrease in a 24 h simulation (79.18 ± 2.68% remaining at 24 h, with 90.51 ± 0.82% remaining at 8 h).[4]

In the solid state, NRCl exhibits a narrow temperature window between melting onset and rapid decomposition: DSC reports onset of melting at 120.7 ± 0.3 °C and a subsequent exothermic event at ~130.8 °C, while qNMR quantifies a steep rise in degradation from 2% at 115 °C to 98% at 130 °C.[4]

One source explicitly frames these data as providing an "explicit upper-temperature limit for processing of NRCl" that can affect supplement production across stages, underscoring the relevance of DSC/qNMR thresholds as hard constraints in heated operations.[4]

NR borate introduces a stabilization strategy motivated by NR reactivity: NR is described as having an especially unstable glycosidic bond joining a positively charged pyridinium heterocycle to a carbohydrate, making it difficult to synthesize, store, and transport, and borate stabilization is described as having high stability against thermal and chemical degradation.[19]

Quantitatively, NR borate solubility is strongly pH-dependent (e.g., 1972.7 ± 15.4 mg·mL⁻¹ at pH 1.5; 926.0 ± 34.4 mg·mL⁻¹ at pH 7.4), and the Arrhenius model is reported to show higher degradation rates at pH 7.4 than at pH 1.5 or 5.0, consistent with influence of HO⁻ concentration.[19]

The same review reports a Gibbs free energy of NR borate degradation of 2.43 kcal·mol⁻¹ and notes that a 10 °C increase approximately doubles degradation rate under any pH condition, echoing a temperature sensitivity observed for NRCl.[4, 19]

NRH exhibits pronounced sensitivity to pH and oxygen: complete degradation in less than one day at pH 5 is reported, while at pH 9 samples show ~42–45% degradation after 60 days, and at 25 °C in DI water under air ~50% degradation is reported after 60 days versus ~27% under N₂.[5]

This oxygen sensitivity is mechanistically attributed to oxidation in the presence of oxygen and to hydrolysis accelerated in acidic conditions, consistent with NRH being described as an unstable molecule due to its N-glycosidic bond and capable of degradation, hydrolysis, and oxidation.[5]

For NMN, quantitative solid-state thermodynamic markers include reported decomposition beginning at 160 °C and completing by 165 °C (with an endothermic DSC peak at 162 °C and enthalpy of decomposition 184 kJ·mol⁻¹), and accelerated stability data reporting decomposition rate of 0.8% per month at 40 °C and 75% RH.[6]

In aqueous solution, NMN degradation is reported as apparent first-order at room temperature with a kinetic equation lg(C_t)=0.0057t+4.8172 and reported times t_0.9=95.58 h and t_1/2=860.26 h, and the study states that degradation rate is primarily influenced by high temperature and pH.[27]

To support practical formulation constraints, one product-focused source recommends incorporation below 45 °C to prevent thermal degradation of the phosphodiester bond and reports less than 5% degradation in accelerated testing at 40 °C/75% RH over 3 months for properly formulated low-water systems.[28]

The primary NMN degradation pathway is described as hydrolysis of the phosphodiester linkage yielding nicotinamide and ribose-5-phosphate, with pH dependencies described as acid-catalyzed hydrolysis below pH 4.5 and base-mediated cleavage above pH 7.5.[28]

4.2 Stilbenoids

Stilbenoids include resveratrol and related compounds that show strong pH- and oxygen-dependent degradation, and their stability in real formulations can deviate from simple Arrhenius extrapolation due to matrix effects and multiple pathways.[7, 12, 29]

In aqueous systems, trans-resveratrol is reported to be stable in acidic pH, while degradation increases exponentially above pH 6.8, and half-life decreases from 329 days at pH 1.2 to 3.3 minutes at pH 10.[12]

At pH 7.4, the kinetics of trans-resveratrol degradation follow first-order kinetics across investigated temperatures, and the activation energy is reported as 84.7 kJ·mol−1.[12]

A mechanistic rationale is given that in acidic pH the hydroxyl groups are protected from radical oxidation by positively charged H₃O⁺, whereas in alkaline conditions phenate ions increase susceptibility to oxidation and phenoxy radical formation, and oxygen in the medium promotes radical reactions leading to degradation.[12]

Independent thermal-stability experiments in aqueous solution (19 mg·L−1) report no significant spectral changes after 30 min up to 70 °C, while more elevated temperatures lead to a general decrease in absorbance at 304 nm and decreased absorbance across 270–350 nm, indicating thermally induced destruction under hydrothermal conditions.[30]

Mechanistic interpretation of those hydrothermal experiments proposes oxidative splitting of the double bond and formation of phenol-containing degradation products such as hydroxy aldehydes, alcohols, and hydroxy acids, and FTIR bands are interpreted as consistent with aldehyde and carboxylic acid formation at 100–120 °C.[30]

In tablet matrices, resveratrol degradation is reported to follow first-order monoexponential kinetics with k values of 0.07140, 0.1937, and 0.231 months−1 at 25, 30, and 40 °C, respectively, but the ln(k) vs 1/T relationship is nonlinear and classified as super-Arrhenius, with the authors proposing possible second reactions, multiple reaction pathways, or matrix effects at higher temperatures.[7]

The same work emphasizes that Arrhenius extrapolation does not always allow determination of degradation kinetics for resveratrol in supplements and that accelerated tests can lead to incorrect estimates, including overestimation of degradation.[7]

For stilbene-like phenolics in dry systems, thermal treatments such as steam sterilization at 121 °C for 20 min produce measurable losses (e.g., pinosylvin decreased 20.98% by peak area), and 24 h oven drying at 105 °C produces >50% decreases in peak area for several phenolics, while TGA indicates decomposition onset temperatures above ~200 °C for pinosylvin systems.[31]

4.3 Flavonoids

Flavonoids show multi-pathway degradation sensitivity influenced by pH, temperature, oxygen, and formulation interactions such as protein binding, and their thermal behavior in DSC/TGA can involve overlapping decomposition and softening rather than simple melting.[9, 22, 24]

In buffered solutions, increasing medium pH from 6.0 to 7.5 increases fisetin and quercetin degradation rate constants by 24-fold and 12-fold, respectively (e.g., fisetin k from 8.30×10−3 to 0.202 h−1; quercetin k from 2.81×10−2 to 0.375 h−1), and raising temperature above 37 °C increases k substantially (e.g., fisetin k to 0.490 h−1 at 65 °C; quercetin k to 1.42 h−1 at 65 °C).[24]

Protein co-ingredients can mitigate degradation: with protein addition, measured k values decrease, including fisetin k decreasing from 3.58×10−2 to ranges down to 1.76×10−2 h−1 and quercetin k decreasing from 7.99×10−2 to ranges down to 3.80×10−2 h−1.[24]

Mechanistically, flavonoid chemical instability is attributed to hydroxyl groups and an unstable pyrone structure, and stabilization by proteins is attributed mainly to hydrophobic interactions (with SDS disrupting stabilization), with hydrogen-bond contributions highlighted as requiring future quantitative assays.[24]

For quercetin at 90 °C near neutrality, degradation kinetics show strong pH effects: k increases approximately five-fold from pH 6.5 to 7.5, and oxidation intermediates such as quercetin quinone are detected, with typical end products including protocatechuic acid (PCA) and phloroglucinol carboxylic acid (PGCA).[22]

The mechanistic narrative assigns the first measurable loss at 370 nm to conversion of quercetin into quinone and suggests that cleavage of the quinone skeleton yields simpler phenolics with limited absorbance, while alkaline deprotonation accelerates oxidation affecting the C-ring and B-ring o-diphenol structure.[22]

In high-temperature systems (150 °C), quercetin degradation and oxidation proceed quickly, with reported rate constants 0.253 h−1 in nitrogen and 0.868 h−1 in oxygen and a strong acceleration (7.17 h−1) in oxygen plus cholesterol; experimentally, quercetin loss increases from 7.9% at 10 min (N₂) to 20.4% at 10 min (O₂), while in cholesterol + oxygen quercetin decreases to 10.9% remaining after 10 min.[26]

Thermal analysis further indicates that quercetin shows a small endothermic peak in the 90–135 °C range associated with a small mass loss (0.86 ± 0.33 wt.%), decomposition initiates at 230 °C, and a prominent DSC endotherm at 303 °C overlaps with decomposition; hydrogen bonding is argued to both constrain melting-like behavior and facilitate decomposition by weakening chemical bonds.[9]

For rutin (a quercetin glycoside) and its fatty-acid esters, TGA indicates rutin is thermally stable up to 240 °C, while esters exhibit lower initial degradation temperatures (217–220 °C) and higher mass loss in a major stage, and activation energies vary with conversion degree from 65 to 246 kJ·mol−1.[8]

4.4 Curcuminoids

Curcumin degradation is strongly pH-dependent and involves oxidative pathways under many aqueous conditions, while thermal decomposition and formulation interactions can shift degradation onsets and apparent kinetic parameters.[10, 18, 32]

In buffer/methanol mixtures at 37 °C, curcumin degradation is reported to follow first-order kinetics with k_obs increasing dramatically as pH increases (e.g., 3.2×10−3 h−1 at pH 7.0 vs 693×10−3 h−1 at pH 12.0), while at pH 5.0 curcumin is stable in the reported experiments.[10]

At pH 8.0, Arrhenius analysis yields (E_a)=79.6±2.2 kJ·mol−1, and extrapolation to aqueous buffer suggests rapid loss under oxidizing conditions (k_obs 280×10−3 h−1, t_(1/2)=2.5 h).[10, 32]

Micellar nanoformulations dramatically slow degradation: in polymeric micelles and Triton X-100 micelles at pH 8.0 and 37 °C, reported k_obs values decrease to 0.9×10−3 and 0.6×10−3 h−1, with half-lives of 777 ± 87 h and 1100 ± 95 h, which are stated to be ~300–500 times higher than free curcumin in aqueous buffer.[10]

Mechanistically, the included work argues that curcumin degradation does not proceed via hydrolytic chain scission but via oxidation yielding a bicyclopentadione as final product, with degradation of 1 mol curcumin associated with consumption of 1 mol O₂ and with the first step being deprotonation of hydroxyl groups at pH above 7.0.[10]

A separate GI-relevant stability study reports apparent first-order kinetics with high linearity (r² > 0.95) and provides activation energies (in kcal·mol−1) that vary with medium (higher at pH 7.4 than in 0.1 N HCl), and it reports that after 12 h at 37 °C, over 80% remained in 0.1 N HCl but only 57% and 47% remained in pH 6.8 and 7.4 phosphate buffers, respectively.[11]

At high temperatures (180 °C), roasting experiments show extreme thermolability, with only 30% of initial curcumin remaining after 5 minutes, and mechanistic interpretation links oxidative cleavage to ferulic acid intermediacy and a decarboxylation step accelerated by air exposure and higher temperatures.[33]

Thermal-decomposition studies of curcumin and curcumin-containing polymer systems under nitrogen show complex behavior: raw curcumin decomposition begins around 240 °C, while incorporation of curcumin into PGA/PCL blends shifts the PGA degradation maximum to lower temperatures (e.g., from 372 °C for neat blend to 327 °C at 5% curcumin), implying that incorporation of curcumin can reduce matrix thermal stability.[18]

The same polymer-focused study links these results to manufacturing relevance by stating that melt state processing requires both chemical stability of the polymer matrix and biological activity of incorporated drugs to be guaranteed and that processing of PGA or PGA/PCL blends with curcumin should be carried out at as low a temperature as possible to prevent PGA degradation.[18]

Curcumin stabilization under high-shear emulsification is also quantified in Pickering emulsions prepared using a high-shear mixer at 22,000 rpm for 2 min: storage at 20 °C in the dark shows that in an unencapsulated curcumin-oil blend approximately half the curcumin is degraded after 6 days and only 20% remains after 16 days, whereas a Pickering emulsion system retains ~50% after 16 days and extends half-life from 13 days to 28 days.[1]

Under UV exposure (6 W, 365 nm), the same system shows ~50% degradation after 9 h and only 20% remaining after 24 h for the oil blend, while the Pickering emulsion retains ~70% after 9 h and ~45% after 24 h and extends half-life from ~13 h to ~27 h for 50% loss.[1]

4.5 Summary table

The table below consolidates representative kinetic and thermodynamic parameters reported across compound classes, emphasizing values most directly usable for process modeling.

5. High-shear manufacturing unit operations

High-shear manufacturing exposes thermolabile compounds to mechanical stress fields that can increase temperature, oxygen transfer, and interfacial area, thereby affecting both reaction kinetics and dominant mechanisms, particularly for oxygen- and pH-sensitive bioactives.[13, 14, 17]

5.1 Melt processing

Melt-state processing is highlighted in polymer–drug systems as a scenario where both polymer stability and drug activity must be preserved, and it is explicitly stated that melt state processing implies that chemical stability of the polymer matrix and biological activity of incorporated drugs must be guaranteed.[18]

In the PGA/PCL–curcumin system, incorporation of curcumin adversely affects PGA thermal stability, and the authors recommend processing at as low a temperature as possible to prevent PGA degradation, linking thermal-stability characterization to process design.[18]

5.2 High-pressure homogenization and microfluidization

High-pressure homogenization subjects fluids to high mechanical stress when they flow through a narrow gap valve; at the orifice, a fluid is subjected to shearing action and additional phenomena such as cavitation, turbulence, collision, and impingement contribute to shearing effects.[14]

HPH operates at elevated pressures of more than 100 MPa and can generate pressures up to 400 MPa, and the pressure applied, number of cycles/passes, and inlet temperature are described as key factors affecting extractability and stability of phytochemicals.[14]

Quantitatively, the HPH review reports example compositional changes such as gradual decreases in L-ascorbic acid (1.7%, 4.6%, 10.7%) at 100, 200, 300 MPa and polyphenol decreases (e.g., 10.6%, 6.0%, 1.4%) in apple juice at 100, 200, 300 MPa, illustrating that pressure level can correlate with losses in oxidation-sensitive compounds depending on matrix and enzyme activity.[14]

At the formulation scale, microfluidization can produce stable emulsions with quantified retention of phenolics: for W/O/W emulsions, optimum microfluidizer conditions were reported as 148 MPa and seven cycles yielding droplets of 105.3 ± 3.2 nm and PDI 0.233 ± 0.020, and after 35 days phenolic retention was 68.6% with antioxidant activity retention 89.5%.[2]

A separate encapsulation study reports a combined high-shear and microfluidization approach: liposomal dispersions were homogenized at 9500 rpm for 10 min and then passed five times through a microfluidizer at 25,000 psi prior to spray drying, demonstrating that industrially realistic sequences may combine shear and subsequent thermal drying.[3]

Ultra-high pressure homogenization (UHPH) reviews emphasize extreme shear and impacts within the valve, with reported conditions such as fluids pumped at more than 200 MPa (typically 300 MPa) and less than 0.2 s residence time in the valve at Mach 3, and with nanofragmentation of microorganisms, colloids, and biopolymers to 100–500 nm.[34]

5.3 High-shear mixing

High-shear mixing is often used as a pre-emulsification or dispersion step and can itself generate significant temperature rises and oxidative environments, thereby influencing degradation even before downstream operations.[13]

In a beverage model, high-shear homogenization for 10 min at increasing rotational speeds increased outlet temperature (from 4.1 ± 0.7 °C at 0 rpm to 41 ± 1.2 °C at 20,000 rpm) and was associated with substantial ascorbic-acid loss (42.6% reduction at 20,000 rpm).[13]

In a curcumin Pickering emulsion system, high-shear mixing at 22,000 rpm for 2 min was used to form emulsions, after which stability improvements were quantified via slower degradation and extended half-life under both storage and UV stress, linking high-shear interfacial structuring to chemical stability outcomes.[1]

5.4 Mechanochemical milling

Mechanochemical processing (e.g., ball milling) can produce amorphous solid dispersions and alter stability by changing solid-state form, mixing at the molecular level, and enabling strong intermolecular interactions such as hydrogen bonding.[15]

For fisetin ASDs and inclusions, milling was performed at room temperature with frequency 30 Hz and time 20 min, and subsequent TG/DSC analysis was performed under nitrogen to quantify thermal stability and Tg behavior.[15]

5.5 Spray drying

Spray drying is described as one of the most commonly used techniques for producing dried vegetable extracts, and high temperatures during spray drying are stated to have potentially detrimental effects on thermolabile (poly)phenols.[3, 20]

In one polyphenol encapsulation study, spray drying was performed with inlet air temperature 150 ± 5 °C and outlet temperature 90 ± 5 °C, while the authors state that the amount of (poly)phenols decreased owing to oxygen and heat exposure during spray drying, motivating encapsulation to preserve functional properties.[3]

In an extract preformulation study, spray-dryer process conditions (inlet temperature, feed flow rate, colloidal silicon dioxide ratio) were evaluated for their effects on responses, and Arrhenius methods were used to determine decomposition kinetic parameters including reaction order, decomposed fraction time, and rate constant.[20]

5.6 Summary table

The table below summarizes stress profiles and example quantitative impacts reported for unit operations that impose high shear and/or intense thermal exposure.

6. Integrated stability–process models

The included sources provide building blocks for an integrated predictive framework in which stability outcomes are computed from unit-operation thermal histories and physicochemical microenvironments (pH, oxygen, water activity) while respecting thermodynamic transition thresholds.[4, 14]

6.1 Time–temperature–shear mapping

A practical mapping approach can use kinetics (k, (E_a), half-life) together with measured or inferred unit-operation time–temperature profiles to compute expected conversion, while using state-transition thresholds (Tg, melting onset, decomposition onset) as boundaries that may shift mechanisms or increase rates.[4, 15]

For example, a pseudo-first-order solution-phase model for NRCl can be parameterized using Arrhenius activation energies (75.4–82.8 kJ·mol−1) and the observation that a 10 °C increase approximately doubles k_obs, allowing translation from validated buffer experiments to short thermal excursions in manufacturing.[4]

For curcumin, temperature sensitivity can be parameterized using (E_a)=79.6±2.2 kJ·mol−1 at pH 8.0 and the reported strong dependence of k_obs on pH, which together enable prediction of losses during aqueous holds or warmed emulsification steps where local pH is neutral-basic.[10]

For trans-resveratrol, pH-driven half-life collapse (from hundreds of days to minutes as pH increases) implies that stability outcomes during processing may be dominated by microenvironmental pH rather than bulk temperature, and Arrhenius modeling at pH 7.4 can be used for modest-temperature exposures with (E_a)=84.7 kJ·mol−1.[12]

6.2 QbD and design space

Quality-by-design interpretation is supported by studies that explicitly evaluate how process parameters and formulation matrices alter degradation mechanisms, including findings that accelerated testing may fail to predict shelf life when non-Arrhenius behavior or matrix effects occur.[7, 29]

For resveratrol tablets, the conclusion that Arrhenius approaches can overestimate degradation in accelerated tests motivates defining design spaces using both mechanistic understanding and multi-temperature data rather than a single accelerated condition.[7, 29]

For spray-dried flavonoid marker systems, excipients are explicitly reported to influence kinetic order and time-to-fraction-decomposed values, indicating that formulation composition is part of the stability design space rather than a fixed background.[20]

6.3 PAT and analytical specificity

Accurate process monitoring requires analytical specificity because degradation products can confound simpler spectroscopic assays, particularly for polyphenols.[12]

For trans-resveratrol, HPLC and UPLC specificity is reported as confirmed while UV/VIS spectroscopy resulted in falsely higher trans-resveratrol concentrations under conditions where it was not stable (alkaline pH, light, increased temperature), emphasizing the need for stability-indicating methods in process analytics.[12]

7. Mitigation strategies

Mitigation approaches in the included sources emphasize restricting exposure to known accelerants (heat, oxygen, high pH, UV), and using formulation architectures that reduce molecular mobility, shield interfaces, or place the active in less reactive microenvironments.[10, 13, 17]

7.1 Encapsulation and dispersions

Encapsulation in micellar or particulate systems can substantially stabilize thermolabile compounds by limiting contact with water, oxygen, and reactive species and by altering acid–base accessibility of key functional groups.[1, 10]

For curcumin, micellar solubilization reduces k_obs to 0.6–0.9×10−3 h−1 and extends half-life to 777–1100 h, and this stabilization is attributed to prevention of hydroxyl deprotonation within a hydrophobic micelle core, which is described as the first step of degradation.[10]

Pickering emulsions provide a physical barrier: the presence of a dense physical barrier at the interface is stated to hinder curcumin degradation, and quantitatively the barrier-forming system extends storage half-life from 13 days to 28 days and UV half-life from ~13 h to ~27 h.[1]

Cyclodextrin-derived carrier systems provide another strategy: resveratrol–β-cyclodextrin clathrates show thermal events including water release near 50 °C and higher-temperature degradation events, and binding free energies (e.g., −86 kJ·mol−1 by MM/PBSA) quantify strong inclusion interactions.[25]

Nanosponge encapsulation of resveratrol eliminates its DSC melting endotherm and provides photoprotection: free resveratrol shows 59.7% degradation within 15 min under UV exposure while resveratrol nanosponges provide approximately two-fold protection, consistent with encapsulation preventing direct UV exposure.[16]

Amorphous solid dispersions can be engineered via mechanochemical milling, and hydrogen bonding between fisetin and Eudragit® ester groups is explicitly identified, providing a mechanistic basis for miscibility and altered Tg that can stabilize against crystallization-dependent changes in dissolution behavior.[15]

Excipient and carrier selection

Excipient selection can alter kinetic mechanisms and stability outcomes, as reported in spray-dried plant-extract systems where reaction order and decomposed-fraction times differ by excipient mixtures, indicating excipient-dependent degradation kinetics.[20]

Protein co-ingredients can stabilize flavonoids via hydrophobic interactions, lowering k values for fisetin and quercetin, and SDS disruption of these interactions supports the interpretation that hydrophobic binding is a key stabilizing mechanism.[24]

Process engineering controls

Process controls that reduce thermal exposure and oxygen contact are directly supported by multiple datasets.[5, 18]

For NRCl, DSC/qNMR evidence indicates that exceeding the melting onset region (~120–130 °C) can produce extremely rapid degradation, supporting hard upper bounds on temperature and residence time in heated solid-state operations.[4]

For NRH, the difference between air and N₂ half-life at 25 °C implies that inerting and oxygen exclusion can be material, and the authors report that samples under an N₂ blanket at 4 °C show no detectable degradation after 60 days while samples at 4 °C in air show ~10% degradation.[5]

For high-shear homogenization, the direct observation that increasing rpm increases outlet temperature and is associated with higher loss of oxidation-sensitive ascorbic acid supports engineering measures that limit shear-driven heating (e.g., cooling jackets, shorter mixing times, staged addition).[13]

For spray drying, the assertion that oxygen and heat exposure decrease (poly)phenols and that high temperatures may be detrimental to thermolabile phenolics supports choices such as lowering outlet temperature when feasible and using encapsulation to reduce oxidation and heat sensitivity.[3]

Antioxidants and oxygen management

Antioxidant and oxygen-management strategies are mechanistically supported across polyphenol datasets.[12, 22]

For quercetin at 90 °C, antioxidants such as cysteine reduce k, with 200 μmol·L−1 cysteine producing a k reduction of ~43% compared to control, and mechanistic interpretation considers stabilization of quercetin quinone and radical quenching effects.[22]

For trans-resveratrol, oxygen is explicitly reported to promote radical reactions leading to degradation, supporting inert processing atmospheres or oxygen barriers where feasible for alkaline/neutral aqueous processing.[12]

In liposomal systems, resveratrol is reported to limit stigmasterol oxidation by neutralizing free radicals and to integrate into lipid bilayers increasing rigidity, reducing permeability to oxygen and oxidizing agents, thereby enhancing thermal and oxidative stability of the system.[35]

Discussion

Across the evidence base synthesized here, the strongest quantitative pattern is that chemical microenvironment (pH, oxygen, water presence) can dominate stability outcomes even at modest temperatures, and that several bioactives exhibit sharp stability discontinuities at specific thermal-transition thresholds.[4, 5, 12]

For NAD⁺ precursors, the NRCl dataset highlights a dual regime: in aqueous solution, pseudo-first-order hydrolysis can be modeled with Arrhenius activation energies and a roughly twofold rate increase per 10 °C, while in the solid state a narrow region around 120–130 °C corresponds to melting followed immediately by rapid decomposition.[4]

For resveratrol, a dominant process risk emerges from pH sensitivity: half-life collapses from long durations at acidic pH to minutes at high pH, while oxygen promotes radical reactions, indicating that high-shear operations that increase oxygen transfer and local alkalinity could be disproportionately damaging even if bulk temperature remains moderate.[12]

For flavonoids, oxidation via quinone intermediates and pH-dependent deprotonation mechanisms (quercetin) combine with high-temperature oxidation and radical-chain coupling (e.g., oxygen plus cholesterol), suggesting that lipid-containing formulations and oxygen exposure can strongly amplify oxidative loss pathways.[22, 26]

For curcumin, there is a mechanistic tension between hydrolysis-driven narratives (in some GI-buffer work) and autoxidation-driven narratives (in micelle-focused work), but both converge on a strong pH effect and on the protective role of hydrophobic microenvironments and oxygen limitation.[11, 32]

At the unit-operation level, high-shear processes can act primarily as indirect accelerants by generating heat and increasing oxidative susceptibility; this is directly demonstrated in high-shear homogenization where rotational speed increases outlet temperature and coincides with oxidative loss of ascorbic acid.[13]

HPH/UHPH introduce additional complexity because the valve region imposes extreme shear, cavitation, and turbulence, and may generate high local temperatures, although residence times can be very short (e.g., <0.2 s in UHPH descriptions), implying that chemical outcomes may depend on whether degradation is controlled by fast radical processes, diffusion-limited steps, or slower thermal activation steps.[14, 34]

Finally, several sources highlight that stability modeling must be mechanistically validated in the relevant matrix: resveratrol tablet data show non-Arrhenius behavior and matrix effects that limit general Arrhenius extrapolation from accelerated tests, and spray-dried plant-extract markers show excipient-dependent kinetic orders and fraction-decomposed times.[7, 20]

Conclusions

Quantitative thermodynamic transition markers (DSC/TGA) and degradation kinetics (k, t_(1/2), (E_a), conversion-dependent activation energies) provide a process-relevant basis for designing manufacturing conditions that preserve potency of thermolabile longevity compounds and related bioactives.[4, 8, 9]

For NAD⁺ precursors, NRCl exhibits a narrow thermal-processing window near melting followed by rapid decomposition, while aqueous kinetics show pH-dependent pseudo-first-order behavior with activation energies of 75–83 kJ·mol−1 that can parameterize thermal exposure models.[4]

For resveratrol, pH and oxygen are dominant variables, with half-life collapsing from hundreds of days at acidic pH to minutes at high pH, and formulation matrices can produce non-Arrhenius behavior that complicates accelerated-testing extrapolation.[7, 12]

For flavonoids and curcuminoids, oxidation pathways (quinone intermediates for quercetin; autoxidation for curcumin) motivate oxygen control and hydrophobic encapsulation strategies, which are quantitatively shown to extend half-life by orders of magnitude in micellar systems and materially in Pickering emulsions produced under high-shear mixing.[1, 10, 22, 32]

For high-shear unit operations, available evidence shows that shear can elevate temperature and promote oxidation (high-shear mixing) and that valve-based high-pressure processes generate extreme shear and cavitation with pressure, pass count, and inlet temperature as key stress variables; these insights support implementing time–temperature–shear mapping and PAT using stability-indicating analytics.[12–14]

Conflict of interest

The authors declare no conflict of interest.[20]