# Evidence: microenvironmental pH

Parent: — · class: solution behaviour · names merged here: diffusion layer pH; microenvironmental pH; surface pH

7 papers measured or used it, 2 only mentioned it (of 207 kept papers). Papers in year order; each section heading ends with the paper's category / subcategory. Generated by tools/build_evidence.py from registry/concepts.csv and the cards; do not edit.

## 2022 Qi — Improved dissolution of an enteric polymer and its amorphous solid dispersions by polymer salt formation · Dissolution / A. Release mechanism and LoC

[2022-qi-enteric-polymer-salt-hp50-miconazole-asd-dissolution](../../../cards/2022-qi-enteric-polymer-salt-hp50-miconazole-asd-dissolution/paper.html) · Dissolution / A. Release mechanism and LoC · used · as: surface pH

| id | kind | content | locator |
|---|---|---|---|
| R18 | record, cited | surface pH near a dissolving enteric polymer — HP-50 films in phosphate buffer of similar buffer capacity (Harianawala 2002, ref 5) — pH gradient reported; surface pH about 0.4 units lower than bulk pH | p.7, p.8 |
| C23 | claim, prior hypothesis, authors: "It is well established"; "may differ" | HPMCP is extensively ionized and soluble at pH 6.8 given its pKa of 4.2, but the pH at the dissolving surface may differ from the bulk pH [rests on: cited: refs 20, 21] | p.7 |
| C24 | claim, prior hypothesis, authors: asserted; "may be generated" | When acidic molecules dissolve above their pKa, ionization liberates protons and lowers the interfacial pH, which can reduce solubility and dissolution; protons leave by diffusion, by neutralization with hydroxyl ions from the bulk or via proton carriers (buffer species); finite diffusion times can create a surface-to-bulk pH gradient set by hydrodynamics, solute pKa and solubility and buffer pKa and concentration; such gradients have been shown for small molecules and enteric polymers, including HP-50 films in phosphate of similar buffer capacity [rests on: cited: refs 4, 5, 22-26; R18] | p.7 |
| C27 | claim, mechanism, authors: asserted ("will have"; "will be more effective"; "cannot act") | BIS-TRIS (pKa 6.5) and phosphate (7.2) bind protons at the lower surface pH and release them at bulk pH; with a surface pH about 0.4 units below bulk, BIS-TRIS has more conjugate base at the surface than phosphate and so conveys protons better; tris (8.1) and TEA (10.2) are mostly protonated at both surface and bulk pH and cannot act as proton carriers, which slows polymer dissolution [rests on: R2, R18; pKa in B1] | p.8 |
| C30 | claim, mechanism, authors: asserted ("will also be affected") | Surface pH also affects gel-layer hydration, with less hydration at lower ionization, and the gel-layer solvent fraction determines the polymer disentanglement rate [rests on: cited: ref 28] | p.8 |
| X16 | extractor note | claim-data gap — The abstract states that polymer solubilization via ionization was "identified" as the rate-limiting step (C2, unhedged), while the discussion says "likely"; the evidence is indirect (rate versus buffer species, buffer capacity, salt form and nominal ionization); surface pH, proton flux and gel-layer hydration were not measured; the carrier argument (C27) uses calculated pKa values (Table 1) and a cited surface pH shift (R18) — C2, C27, C31, R18 — treat the rate-limiting step as the authors' interpretation of rate data |  |

## 2023 Bapat — Does Media Choice Matter When Evaluating the Performance of Hydroxypropyl Methylcellulose Acetate Succinate-Based Amorphous Solid Dispersions? · Dissolution / A. Release mechanism and LoC

[2023-bapat-hpmcas-asd-media-choice-buffer-capacity-release](../../../cards/2023-bapat-hpmcas-asd-media-choice-buffer-capacity-release/paper.html) · Dissolution / A. Release mechanism and LoC · measured · as: microenvironmental pH

| id | kind | content | locator |
|---|---|---|---|
| R15 | record, measured | gel layer apparent pH (mean ± SD) — gel removed from compacts after exposure in the IDR apparatus (P10) — sub-table below | p.5720; methods p.5717-5718 |
| R16 | record, measured | normalized release rate plotted against gel layer apparent pH — HPMCAS in 25, 50, 100 mM pH 6.8 and 50 mM pH 7.5 phosphate; HPMCAS-TEA in 50 mM pH 6.8 phosphate (labels in figure) — HPMCAS: gel pH 5.6, 6.0, 6.2, 6.3 (R15.b-e) against rates ≈0.60, ≈0.90, ≈1.01, ≈1.09 (the R5.c-e and R5.l media); HPMCAS-TEA: gel pH 6.7 against ≈1.62; x error bars ≈±0.10-0.15 pH, y error bars ≤≈0.04 (read from Fig. 10); the glycine point (R15.f) is not plotted | Fig. 10, p.5723 |
| C38 | claim, mechanism, authors: "probable" | At a bulk pH of 6.8 a lower pH exists at the polymer-solution interface, set up by protons released as the polymer ionizes, which lowers polymer solubility and flux (eq 2) [rests on: R15; R26; E2] | p.5723 |
| C39 | claim, mechanism, authors: "strongly supported"; "expected"; "as confirmed by gel layer pH measurements" | The lower interfacial pH is supported by the gel-layer measurements; more buffer species carry more protons to the bulk and lessen the interfacial pH drop, and changing bulk pH or buffer system changes base and proton-carrier concentrations and hence interfacial pH [rests on: R15] | p.5723 |
| C51 | claim, conclusion, authors: asserted ("highly correlated"; "substantially lower"); abstract: asserted | Polymer release rate was highly correlated with gel-layer pH, which was substantially lower than bulk pH [rests on: R15, R16] | p.5714; p.5724 |

## 2023 Nguyen — Fed- and Fasted-State Performance of Pretomanid Amorphous Solid Dispersions Formulated with an Enteric Polymer · Bioperformance / Bioperformance

[2023-nguyen-pretomanid-hpmcas-asd-fed-fasted-performance](../../../cards/2023-nguyen-pretomanid-hpmcas-asd-fed-fasted-performance/paper.html) · Bioperformance / Bioperformance · used · as: microenvironmental pH

| id | kind | content | locator |
|---|---|---|---|
| C26 | claim, prior hypothesis, authors: "is expected" | HPMCAS-HF dissolves only when a critical fraction of its carboxylic acid groups is ionized, i.e. above a threshold pH; adding a base is expected to speed polymer dissolution, and hence drug release, by raising the microenvironmental pH [rests on: cited: refs 29, 42] | p.3176 |

## 2024 Bapat — Interplay of Drug−Polymer Interactions and Release Performance for HPMCAS-Based Amorphous Solid Dispersions · Dissolution / A. Release mechanism and LoC

[2024-bapat-hpmcas-drug-polymer-complexation-release-performance](../../../cards/2024-bapat-hpmcas-drug-polymer-complexation-release-performance/paper.html) · Dissolution / A. Release mechanism and LoC · used · as: microenvironmental pH

| id | kind | content | locator |
|---|---|---|---|
| R15 | record, measured release; gel-layer pH cited (ref 46 for 50 mM pH 6.8; source of other two values not stated) | normalized release rate (component not labelled) versus gel-layer pH (n = 3, horizontal and vertical error bars) — LOR/HPMCAS 25:75 ASD in three buffers, P7 — 50 mM pH 6.8 phosphate: gel-layer pH ≈6.0, rate ≈0.12; 100 mM pH 6.8 phosphate: ≈6.2, ≈0.29; 50 mM pH 7.5 phosphate: ≈6.3, ≈0.68 (read from Fig. 13); text: steep rise of release rate over gel-layer pH 6.0-6.3 | Fig. 13, p.1475; text p.1475 |
| R20 | record, cited | surface or gel-layer pH of dissolving HPMCAS — HPMCAS compacts (ref 46) — 50 mM pH 6.8 phosphate: gel layer estimated at pH 6.0; 50 mM pH 9.0 glycine/NaOH: no gel layer formed, surface pH lower than 5.5 | p.1469, p.1470 |
| C9 | claim, assumption, authors: asserted | Complexation tests at pH 6.0 mimic the pH at the HPMCAS gel layer-bulk solution interface, which is lower than the bulk pH from proton release on HPMCAS ionization; for 50 mM pH 6.8 phosphate the gel layer was estimated at pH 6.0, the relevant pH for complexation that affects release [rests on: R20; cited: ref 46] | p.1469 |
| C40 | claim, mechanism, authors: "can be attributed" | The gel-layer pH, not the bulk pH, is relevant: complexation is negligible at bulk pH 6.8, yet ASD release is substantially compromised there, attributable to the much lower gel-layer pH where some complexation occurs and slows polymer dissolution; the steep rise of release over gel-layer pH 6.0-6.3 corresponds to a steep part of the complexation-pH curve [rests on: R13, R15, R4.j, R4.l; cited: ref 46] | p.1475 |
| C48 | claim, generalisation, authors: "likely" | The boundary-layer pH is likely lower than the bulk pH, which matters when predicting drug ionization from pKa [rests on: R20; cited: ref 46] | p.1476 |

## 2025 Bapat — Impact of HPMCAS Grade on the Release of Weakly Basic Drugs from Amorphous Solid Dispersions · Dissolution / A. Release mechanism and LoC

[2025-bapat-hpmcas-grade-weak-base-asd-release-complexation](../../../cards/2025-bapat-hpmcas-grade-weak-base-asd-release-complexation/paper.html) · Dissolution / A. Release mechanism and LoC · measured · as: surface pH

| id | kind | content | locator |
|---|---|---|---|
| M3 | material | HPMCAS-LF HPMCAS AQOAT-LF, Shin-Etsu (Tokyo, Japan) | p.398 |
| M4 | material | HPMCAS-MF HPMCAS AQOAT-MF, Shin-Etsu | p.398 |
| M5 | material | HPMCAS-HF HPMCAS AQOAT-HF, Shin-Etsu | p.398 |
| P10 | method | slurry pH (surface pH) of polymer | p.400 |
| R15 | record, cited | pH at the dissolving ASD surface — HPMCAS ASD, bulk 50 mM phosphate buffer pH 6.8 (ref 8) — pH 6.0 | p.403-404 |
| C10 | claim, assumption, authors: "indicating"; "are taken to represent" | The final slurry pH represents the lowest possible surface pH of the polymer during dissolution; equilibration within 15 min shows the slurries were saturated in pH [rests on: R18] | p.400 |
| C28 | claim, assumption, authors: asserted | pH 6.0 is a relevant condition for complexation because it is the pH at the dissolving ASD surface for a bulk pH of 6.8 in 50 mM phosphate [rests on: R15; cited: ref 8] | p.403-404 |

## 2025 Fagan — Impact of Permeation Enhancers on the Release of Insulin from Tablets in Biorelevant Media · Peptide permeability / Peptide permeability

[2025-fagan-permeation-enhancers-insulin-minitablet-biorelevant-media](../../../cards/2025-fagan-permeation-enhancers-insulin-minitablet-biorelevant-media/paper.html) · Peptide permeability / Peptide permeability · measured · as: microenvironmental pH

| id | kind | content | locator |
|---|---|---|---|
| R5 | record, measured | pH of the saturated suspensions — P2 after P1, n = 3 — sub-table R5 below | Fig. 2 p. 4002; text pp. 4002 and 3999 |
| R19 | record, measured | colour of one drop of M7 on the tablet surface — blank, C10 and SNAC minitablets, P8, no medium present — text: no colour change on the blank tablet, dark green on the C10 tablet, pale green on the SNAC tablet; the printed photograph shows a red-orange blank tablet, a pale green C10 tablet and a yellow-green SNAC tablet against a scale running from pH 4.0 to 10.0 | Fig. 10 p. 4005; text p. 4005 |
| C33 | claim, mechanism, authors: Section 3.2.3: were hypothesized; discussion: compelling evidence to suggest; abstract and conclusions: was determined | the difference in insulin release in the presence of the enhancers comes from a local pH rise at the tablet surface produced by high enhancer concentrations at the solid-solution interface [rests on: R5, R12, R13, R19] | pp. 3999, 4005, 4006 and 4007 |
| C34 | claim, conclusion, authors: potentially reaching | the pH experienced by insulin at the tablet surface could be as high as 9.2 with the fatty acid enhancer and 7.9 with SNAC [rests on: R5] | text p. 4005 |
| C36 | claim, conclusion, authors: This suggested | the colour change puts the surface pH near 8 for the C10 tablets and near 7 for the SNAC tablets, far above the blank tablets [rests on: R19] | text p. 4005 |

## 2025 Kaur — Impact of drug-polymer complexation and media properties on the release performance of amorphous solid dispersions containing a weakly basic drug and hydroxypropyl methylcellulose acetate succinate · Dissolution / A. Release mechanism and LoC

[2025-kaur-bdq-hpmcas-complexation-media-asd-release](../../../cards/2025-kaur-bdq-hpmcas-complexation-media-asd-release/paper.html) · Dissolution / A. Release mechanism and LoC · used · as: surface pH

| id | kind | content | locator |
|---|---|---|---|
| C2 | claim, prior hypothesis, authors: "can" | Proton release from ionizing HPMCAS can make the pH of the unstirred layer at the ASD surface lower than bulk pH, retarding HPMCAS dissolution; molecularly dispersed drug reduces water sorption and impedes polymer dissolution [rests on: cited: refs 14, 15] | p.2 |
| C44 | claim, assumption, authors: asserted | At 5 and 10% DL the BDQ:COOH molar ratio is 0.08:1 and 0.16:1 for HPMCAS-LF, and Fig. 1A shows about 55 and 75% complexation at these ratios at pH 6.0; pH 6.0 is used because the gel-layer surface pH is lower than bulk and the reduced polymer solubility at the interface governs its diffusion [rests on: R5.b, R22; E1; cited: ref 14] | p.10 |
| R22 | record, cited | gel-layer pH of HPMCAS-MF immersed in pH 6.8 phosphate buffer — buffer capacity 13, 26 or 51 mM/ΔpH (ref 14) — 5.6, 6.0 or 6.2 respectively | p.9 |

## Mentioned only

- 2016 Sousa — [2016-almeida-sousa-supersaturation-salt-cocrystal-amorphous-weak-base](../../../cards/2016-almeida-sousa-supersaturation-salt-cocrystal-amorphous-weak-base/paper.html) · Dissolution / C. Amorphous solubility and LLPS (ref C8)
- 2019 Trasi — [2019-trasi-solvent-granulation-ritonavir-lopinavir-asd](../../../cards/2019-trasi-solvent-granulation-ritonavir-lopinavir-asd/paper.html) · ASD process / ASD process (ref C4)