When the stomach decides: gastric pH, enteric polymers and the crystallization of a weakly basic drug from amorphous solid dispersions

Background and motivation

An amorphous solid dispersion (ASD) disperses a poorly soluble drug molecularly in a polymer so that dissolution produces a supersaturated solution, a solution above the crystalline solubility. Such solutions are metastable or unstable and tend to crystallize, and the polymer is chosen partly to delay that crystallization by inhibiting nucleation and crystal growth (Section 1) C6. Amphiphilic, ionizable polymers such as hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose phthalate (HPMCP) are effective at maintaining supersaturation. HPMCAS is the carrier of several marketed ASDs (telaprevir, ivacaftor, vemurafenib, posaconazole, apalutamide), while HPMCP has been used commercially only for itraconazole (Lozanoc) and delamanid (Deltyba) R29.

These are enteric polymers: their acidic groups (phthalyl in HPMCP, succinoyl in HPMCAS) are un-ionized at stomach pH, so the polymer does not dissolve. The introduction notes that this also weakens them as crystal growth inhibitors at low pH; for example HPMCAS-LF inhibited felodipine crystal growth less well at lower pH (Schram et al., ref 24) C7·R26. If a drug can crystallize while the formulation sits in gastric fluid, the polymer's behaviour there matters.

Weakly basic drugs make this worse. They are protonated and comparatively soluble in acid but much less soluble at intestinal pH, so they may dissolve in the stomach and then crystallize on transfer to the small intestine (refs 27–31) C8. Delamanid (DLM), a nitroimidazooxazole used against multidrug-resistant tuberculosis, is such a weak base, with poor solubility and low bioavailability; its absorption depends on food and fed-state dosing is recommended C10. With food, peak gastric pH can rise to about 6.0–7.0 before returning to fasting values after 1–4 h, and pH 6.4, 5.0 and 3.0 are commonly used to represent early, middle and late times after a meal R24. A dosage form can therefore meet anything from strongly acidic to nearly neutral gastric fluid.

The group's earlier study (Van Duong et al. 2022, ref 15) had shown that DLM free base crystallizes readily during ASD manufacture and storage, that salts formed in situ with counterions such as 1,2-ethanedisulfonic acid (the edisylate) are more stable in the amorphous form, and that edisylate ASDs with enteric polymers released more at pH 6.5 than the neat amorphous salt or the free-base ASD C9·R27. What was not known is how these ASDs behave when they first spend time in acid. The marketed DLM product uses an enteric polymer, so the formulation is nominally insoluble in the stomach, yet the ionized drug may leach out of it C11.

The study therefore asks how polymer type and grade (HPMCP-50, HPMCP-55, HPMCAS-LF, -MF and -HF) and drug form (free base or edisylate salt) change release and crystallization when the gastric stage of a two-stage test is set to pH 1.6, 3.0 or 5.0. The working hypothesis is that three things govern the release profile: how easily the drug crystallizes at each pH, the form of the drug in the ASD, and the solubility of drug and polymer as a function of pH C12.

Background concepts

pH-dependent solubility of a weak base. A weak base gains a proton below its pKa; the protonated form is far more soluble, so total solubility rises steeply as pH falls below the pKa. The paper fits its solubility data with the Henderson–Hasselbalch relation for weak bases (the equation itself is not printed) and obtains a pKa of 3.94 ± 0.04, against a reported value of 4.3 M1·E1·R3. The same reasoning applies to both the crystalline and the amorphous drug.

Amorphous solubility and the supersaturation ratio. The amorphous form has a higher free energy than the crystal, so it can reach a higher concentration, the amorphous solubility; above it a separate drug-rich phase forms. The paper measures it by UV extinction: a concentrated DMSO solution of the drug is pumped into the medium until light scattering appears at a non-absorbing wavelength (450 nm) P2. The degree of supersaturation is expressed by the supersaturation ratio (SR), which the paper defines in words:

In plain terms: SR compares the concentration reached with the crystalline solubility at the same pH; above 1 the solution is supersaturated and crystals can form, and the larger SR is, the stronger the driving force for crystallization E2·C36. At the amorphous solubility, SR equals the ratio of amorphous to crystalline solubility, which for DLM at pH 6.5 is 42 R2.

Enteric polymers and their grades. The polymers dissolve once enough acidic groups are ionized, around their pKa and above a "dissolution pH threshold". Table 3 collects cited values: HPMCP-50 pKa 4.20–4.32 and threshold pH 5.0; HPMCP-55 pKa 4.49–4.83 and threshold 5.5; HPMCAS-LF pKa 5.09 and threshold 4.8–5.5; HPMCAS-MF pKa 4.92–5.0 and threshold 5.2–6.0; HPMCAS-HF pKa 5.15 and threshold 5.7–6.8 M4·M5·M6·M7·M8. HPMCP-55 has more phthalyl groups, a higher molecular weight and more acid resistance than HPMCP-50; among the HPMCAS grades LF has the most succinoyl groups and HF the highest ratio of acetyl to succinoyl groups M5·M6·M8.

Salt, pHmax and disproportionation. A salt of a weak base is the stable solid only below a characteristic pH, pHmax; above it the free base is the stable solid, and a salt in contact with the medium can revert to the free base (disproportionation) and then crystallize as the free base C25. Because the free base has to form first, a salt can delay crystallization even when it is not the stable form.

Solution, matrix and surface crystallization. Crystals can form in the supersaturated solution (solution crystallization, seen as a falling concentration) or inside the wetted, undissolved ASD (matrix crystallization). When an ASD particle absorbs water its glass transition temperature falls and molecular mobility rises, which lets a crystallizing drug nucleate within the matrix; the paper argues that for DLM such crystals form mainly at the particle surface C43·C45. Crystals formed this way can later act as seeds when the polymer dissolves and releases them (ref 72) C44.

Two-stage (pH-shift) release test. The tablet is first held in an acidic medium that stands for gastric fluid, then a concentrated buffer is added to bring the pH to the intestinal value. Here the first stage lasts 60 min at pH 1.6, 3.0 or 5.0 and the second 30 min at pH 6.4–6.6 P8.

Methods in detail

The study combines four kinds of work: solubility of drug and polymers across the pH range, two-stage release of drug and polymer from tablets, a search for crystals in the neat salt, the ASD powders and ASD films after acid exposure, and one control experiment that tests whether crystallization happens in the solution. The flow below summarizes how they connect.

Formulations

All ASDs contained 25% drug loading (DL). The edisylate salt ASDs were made in situ: DLM, 1,2-ethanedisulfonic acid and the polymer were dissolved in acetone–dichloromethane (1:1 v/v), the solvent was removed by rotary evaporation at 40 °C, and the product was dried overnight under vacuum, cryo-milled and sieved to 106–250 µm P5. The paper does not state the acid:drug ratio or whether the 25% refers to free base or salt (see Limitations) X12. A free-base ASD could not be made amorphous at 25% DL by rotary evaporation, so the free base was spray dried with HPMCP-50 from methanol–dichloromethane (10% w/v solids, inlet 75 °C, nitrogen 700 L/h, feed 4 mL/min) and dried again under vacuum; its PXRD showed a halo without the drug's crystal peaks P6·R5. The free base was combined only with HPMCP-50, which is the polymer of the marketed product A1.

Because the powders wet poorly, release was tested on 75 mg disintegrating tablets containing ASD equivalent to 5 mg DLM, with sodium starch glycolate (4 mg), croscarmellose sodium (4 mg), silica colloidal hydrate (0.6 mg), magnesium stearate (0.6 mg) and Avicel PH 101 to 75 mg (ref 15) P7.

Solubility of drug and polymers

The media were 0.02 M HCl (pH 1.6) and phosphate buffers from pH 2.0 to 6.5, whose recipes are given in Table 1 (from ref 30) P1. Crystalline solubility was measured by stirring excess drug for 48 h at 37 °C, ultracentrifuging and assaying by HPLC at 320 nm P1. Amorphous solubility came from the UV extinction method described above P2. For the polymers, 50 mg was stirred in 15 mL of each medium for 48 h at 37 °C; after centrifugation the dissolved polymer was hydrolysed with sodium hydroxide, neutralized and its cellulose backbone was assayed by HPLC with evaporative light-scattering detection, with phenol–sulfuric acid colorimetry at 490 nm as a cross-check P3·P4.

Two-stage release

Release was run in a USP apparatus II at 150 rpm and 37 °C, with a dose concentration of 100 µg/mL P8. The single-stage control used 50 mL phosphate buffer pH 6.5. In the pH-shift tests the tablet spent 60 min in 45 mL of 0.02 M HCl (pH 1.6), 47 mL of 0.1 M phosphate buffer pH 3.0 or 48 mL of 0.13 M phosphate buffer pH 5.0; then 5, 3 or 2 mL of a 0.57 M phosphate buffer pH 7.3 brought the volume to 50 mL and the pH to 6.4–6.6 for another 30 min (Table 2) P8. Drug concentration was followed in situ by fiber-optic UV, using the area under the second-derivative spectrum between 330 and 350 nm P9. Polymer release was measured by withdrawing 1.5 mL samples, centrifuging them and assaying by HPLC-ELSD P10. The maximum SR in the acid stage was then computed from the concentration at 1 h and the crystalline solubility at that pH (Figure 9) E2·R13.

Finding crystals

Three kinds of samples were examined. First, the neat amorphous edisylate was stirred in excess in pH 1.6, 3.0, 5.0 or 6.5 media at 37 °C and sampled for powder X-ray diffraction (PXRD) from 5 min up to 4 h (pH 1.6, 3.0), 120 h (pH 5.0) or 96 h (pH 6.5) P11. Second, 20 mg of each ASD powder was stirred in 50 mL of acid for 1 h (the same drug concentration as in the release tests), filtered and examined by PXRD and scanning electron microscopy (SEM) P12·P13·P15. Third, thin ASD films were spin-coated on cover glasses, laid on a drop of acidic medium, and watched by polarized light microscopy (PLM) for 60 min, then imaged by SEM P14·P15. Undissolved particles left after the full two-stage test were also imaged by SEM R21.

The control for solution crystallization

To test whether crystallization in the solution explains the losses, pH 3.0 → 6.5 tests of three salt ASDs (HPMCP-50, HPMCP-55, HPMCAS-MF) were repeated with 1 mg/mL PVPVA dissolved in the medium beforehand. PVPVA had been found earlier to be a good inhibitor of DLM solution crystallization P16·R27. If solution crystallization were the cause, the inhibitor should raise release.

Experimental analysis

The drug dissolves in acid, the polymers near neutral pH

The solubility data set up the whole problem. Both forms of DLM are far more soluble in acid: at pH 1.6 crystalline and amorphous solubility are 10.2 ± 0.6 and 154.5 ± 7.7 µg/mL, at pH 6.5 only 0.018 ± 0.003 and 0.76 ± 0.06 µg/mL R1. Crystalline solubility is thus about 500-fold lower at pH 6.5, and the amorphous solubility at pH 6.5 corresponds to an SR of 42 R2. Between these points amorphous solubility falls to about 60, 22.5 and 9 µg/mL at pH 2.0, 2.5 and 3.0 and to about 1 µg/mL or less from pH 4.0 (read from Figure S1) R1. The Henderson–Hasselbalch curve with pKa 3.94 follows the amorphous data; for crystalline DLM at pH 1.6 it gives about 3.7 µg/mL, well below the measured 10.2 µg/mL R3.

Table A. Solubility at 37 °C at the release-test pH values (values with ± are printed; others read from Figures 1 and S1, approximate) R1·R4.

The polymers were insoluble below pH 4.5 and began to dissolve near their reported thresholds: HPMCP-50 reached 893 ± 95 µg/mL and HPMCP-55 189 ± 18 µg/mL at pH 5.0, HPMCAS-LF and -MF 1687 ± 47 and 1401 ± 69 µg/mL at pH 5.5, and HPMCAS-HF dissolved only from about pH 6.0 R4. The authors relate the HPMCAS ranking to substituent chemistry: LF has more succinoyl groups than MF, HF a higher acetyl to succinoyl ratio C14. They summarize the situation at the test pH values as follows: at pH 1.6 the drug is appreciably soluble and the polymers are not; at pH 3.0 and 5.0 both are poorly soluble; at pH 6.5 the polymers dissolve well and the drug hardly at all C15.

Note by the AI writer (not discussed in the paper). Two details of the polymer data need care. The method adds 50 mg of polymer to 15 mL, which caps any measurable concentration at about 3,300 µg/mL, yet the text prints ">20 mg/mL" at pH 6.5 and Figure 1 plots roughly 4,000–21,000 µg/mL from pH 5.5 or 6.0 upward; some quantity in the method or the axis must be misprinted, and those high values cannot be used as solubilities X1. And the summary "low polymer solubility at pH 5.0" does not fit the HPMCP grades, which dissolve substantially there, as both the 893 and 189 µg/mL values and the polymer release in the pH 5.0 stage show X2.

The free-base ASD

The spray-dried free-base ASD released quickly at pH 6.5: about 48 µg/mL after 1 min and about 85–86 µg/mL between 5 and 30 min, drifting to about 81 µg/mL at 60 min (read from Figure 2A; 100 µg/mL is complete release) R7. An earlier rotary-evaporated ASD of the same composition had released only 20%, which the authors take as confirmation that the spray-dried material was predominantly amorphous R6·C17. After an acid stage, release depended on the pH. From pH 1.6 the concentration reached about 39 µg/mL by 60 min and about 62 µg/mL after the shift; from pH 3.0 it was about 1–2 µg/mL in acid and about 33.5 µg/mL after the shift; from pH 5.0 it stayed at about 7 µg/mL in both stages R7. The polymer itself was not the limitation: HPMCP-50 dissolved to about 102–105% within 5 min of the shift from pH 1.6 or 3.0, and at pH 5.0 about 62–87% dissolved during the acid stage while drug release stayed near 7 µg/mL R8·C18. SEM of free-base films after 1 h showed flakes at pH 1.6, star- and plate-shaped crystals at pH 3.0 and a fine granular surface at pH 5.0, and PLM showed birefringent particles at all three; the authors conclude that the free base crystallized in all simulated gastric fluids R9·R10·C19.

Salt ASDs: the gastric pH and the polymer grade decide the outcome

Table B gathers the drug release of the five salt ASDs at the end of the acid stage and at the end of the test, read from Figures 3 and 4.

Table B. Drug release (% of dose) of the 25% DL salt ASDs, at 60 min (acid) and 90 min (final); read from Figures 3A, 3B and 4A–C (approximate) R11.

At pH 6.5 alone, HPMCP-50, HPMCP-55 and HPMCAS-LF released nearly everything, HPMCAS-MF about 55–57.5% and HPMCAS-HF almost nothing R11.a·R11.e·R11.i·R11.m·R11.q. The acid stage changed the ranking in ways that depend on both polymer and pH. At pH 1.6, where the drug is most soluble, every ASD except HPMCP-55 released 21–36.5% in acid; on transfer the two HPMCP ASDs went to near complete release, whereas the HPMCAS ASDs stayed at or below about 47.5%, and HPMCAS-HF even fell slightly, from about 21 to 18% R11·R23. At pH 3.0 almost nothing dissolved in acid; after the shift HPMCP-55 reached about 80.5% but HPMCP-50 only about 41%, and the HPMCAS ASDs 1–37.5% R11. At pH 5.0 HPMCP-50 released about 80% within 10 min of the acid stage, because its polymer dissolves at that pH, and released nothing further after the shift; HPMCP-55 released nothing in acid and reached only about 12.5%; HPMCAS-LF climbed to about 50% after the shift, while MF and HF stayed near 12.5% and 0% R11·R4.

The authors read this as release depending on the gastric pH and the polymer grade, with none of the HPMCAS ASDs releasing near completely after a pH shift C22·C24. Their abstract states that ASDs with HPMCP "showed improved overall release for all testing conditions" relative to HPMCAS, qualified by "In general" C1. Table B shows one clear exception: after pH 5.0, HPMCP-55 (about 12.5%) released less than HPMCAS-LF (about 50%) X3. The HPMCP-55 result at pH 1.6 is also striking: under 10% of the drug left the tablet in acid, against about 30% for HPMCP-50, although neither polymer dissolves there R11.f·R12.b·R12.f·C40.

Polymer release does not track drug release in acid

Polymer release data (Figures 3C–D and 4D–F) separate polymer dissolution from drug release. At pH 1.6 and 3.0 every polymer released about 10% or less in acid and then dissolved after the shift; for the HPMCP grades this reached about 67–112% by 90 min, the HPMCP-50 values above 100% being as plotted R12. At pH 5.0 both HPMCP grades dissolved during the acid stage, HPMCP-50 at about 70–79% and HPMCP-55 rising more slowly from about 17.5% at 5 min to about 65.5% at 60 min R12.d·R12.h·C23. Yet HPMCP-55 released essentially no drug in that period R11.h. For HPMCAS, polymer release ranked LF > MF > HF, consistent with drug release: at pH 6.5 alone about 94, 45.5 and 29.5% by 60 min, and at the end of the shift tests about 92%, 53–54.5% and 16.5–19.5% R12.i–t·C24. The case of HPMCAS-LF after pH 1.6 shows that dissolving the polymer is not enough: about 92% of the polymer dissolved but only about 47.5% of the drug R12.j·R11.j.

Supersaturation in the acid stage, and the PVPVA control

Table C. Maximum supersaturation ratio after 1 h in the acid stage, read from Figure 9 (approximate) R13.

SR rose from pH 1.6 to pH 5.0 for every ASD (Table C) R13·C35. At pH 1.6 the concentrations were the highest, but so was the crystalline solubility, so SR stayed between about 0.9 and 3.8; the authors note that most ASDs, but not all, supersaturated the acid C34. At pH 5.0 three ASDs reached about 42, the limit set by the amorphous solubility C35·R2. Supersaturation is the driving force for crystallization, so one might expect the most supersaturated systems to fail most C36.

The data say otherwise. Concentrations did not generally fall during the acid stage, so there was little sign of desupersaturation in the medium R23·C37. With PVPVA predissolved, the pH 3.0 → 6.5 results were essentially unchanged: about 44 versus 41% for HPMCP-50, about 82 versus 80.5% for HPMCP-55 and about 7 versus 10% for HPMCAS-MF (Figure S6) R22. And at pH 3.0, where SR differed relatively little between ASDs, final release ranged from about 1% to 80.5%; HPMCP-55 (SR about 7.5) and HPMCAS-MF (SR about 7.0) ended at about 80.5% and 10% R13·R11·C39. The authors conclude that solution crystallization in the acid stage was not the predominant failure mechanism, and suggest that the small amount of polymer dissolved at every pH "may" be what kept it low, cellulose derivatives being strong inhibitors of DLM solution crystallization C37·C38·C39.

Note by the AI writer (not discussed in the paper). The released concentrations often exceed the amorphous solubility by a wide margin: about 81–101 µg/mL at pH 6.5 against an amorphous solubility of 0.76 µg/mL, and about 80% of the dose for salt HPMCP-50 in the pH 5.0 acid stage, where the amorphous solubility is about 1 µg/mL or less R7·R11·R1. The SR of about 42 shown for these ASDs at pH 5.0 equals the amorphous to crystalline ratio, so SR appears to be capped at the amorphous solubility. The paper does not explain how SR was computed in this case, nor in what physical state the drug above the amorphous solubility was (for example as colloidal drug-rich particles); the "release" values are best read as total drug detected by the UV probe X9.

The neat salt becomes crystalline free base

Suspended on its own, amorphous DLM edisylate did not survive acid. At pH 1.6, diffraction peaks at about 5.3°, 17.5°, 21° and 28° 2θ appeared within 5 min and by 4 h matched the reference pattern of crystalline DLM free base; at pH 3.0 a weak peak was visible at 5–15 min and several peaks at 1 h; at pH 5.0 and 6.5 the pattern stayed amorphous for at least 4 h, with weak peaks from about 14 h and clear free-base peaks from 24 h (pH 6.5) or 72 h (pH 5.0) (Figure 5) R14. The authors conclude that pHmax lies below 1.6, so the free base is the stable solid at every pH studied and the amorphous salt disproportionates and then crystallizes as free base; the speed of conversion agrees with the small supersaturation the neat salt gave at pH 1.6 in earlier work C25·C26. Conversion was slower at pH 5.0 and 6.5, "likely due to" a lower driving force for dissolution at the lower solubility C27.

Crystals on the ASDs after one hour in acid

PXRD of the ASD powders after 1 h in acid showed only amorphous halos, with none of the free-base peaks (Figure 6); PXRD typically detects about 1–5% crystallinity, so any crystal fraction was small R15·R16. Microscopy told a different story. Fresh particles had smooth faces (Figure S3) R17. After 1 h, HPMCP powders were unchanged at pH 1.6; HPMCP-50 carried small particles at pH 3.0 and was covered by small agglomerates at pH 5.0; HPMCP-55 showed crystals at pH 5.0 to a lower extent; the HPMCAS powders became pitted and porous, most of all HF, with crystal agglomerates that increased with pH (Figure 7) R18·C28. Films gave the clearer picture (Table D).

Table D. Salt ASD films after 1 h in acid: authors' statements and the AI writer's reading of the SEM (Figure 8) and PLM (Figure S5) images R19·R20.

The authors summarize the films as agreeing with the powders: HPMCP films were unchanged at pH 1.6, the HPMCAS-HF film crystallized even at pH 1.6, every film except HPMCP-55 crystallized at pH 3.0, and at pH 5.0 the surfaces were covered with crystals smaller than those at pH 3.0 C30. After the full two-stage test, undissolved particles of all ASDs were covered in small crystals within 30 min at pH 6.5 (Figure S4) R21·C29. Overall, they conclude, crystallization in acid was more extensive with HPMCAS than with HPMCP C4.

Discussion

The authors' explanation

The discussion assembles these observations into one chain, drawn schematically in Figure 10. In the acid stage the enteric polymer stays largely undissolved, but the ionized drug leaches out; despite the low polymer solubility at pH 1.6, the authors report notable drug release there (the same has been seen for posaconazole, clotrimazole, ketoconazole and itraconazole) C33·R25. Because crystallization from solution is ruled out, the failures must originate in the undissolved ASD: water absorbed by the particle lowers its glass transition temperature and raises mobility, and the drug crystallizes in the matrix, "likely" mainly at the surface C43·C45. These crystals, few as they are, are "potentially catastrophic" once the pH rises: as the polymer ionizes and dissolves, amorphous drug near the crystal seeds crystallizes too, so that "there appear to be two competing processes, drug crystallization and drug release" C44·C46·C49.

Several observations support the chain. Surface crystals after pH 1.6 "largely correlate" with the release after transfer: the HPMCP films stayed clear and the HPMCP ASDs released nearly completely, while HPMCAS-HF crystallized and released little C48·R19·R11. Once drug entered the solution after the shift its concentration stayed constant, which the authors read as seed growth in the bulk being "likely limited" by dissolved polymer, consistent with polymer adsorption on crystal surfaces (step pinning) C50·R23.

What decides whether a formulation survives

The authors name three modifiers. First, the drug form: no surface crystals formed on salt HPMCP films at pH 1.6, whereas the free-base film did crystallize, and the salt matched or outperformed the free base at every gastric pH C51·C2. Since the crystals seen with the neat salt were free base, the authors propose that the salt "likely" hinders crystallization because it must first convert to the free base, a kinetic advantage that gives slower crystal formation in acid and better release after transfer C52. Second, polymer solubility in the acid stage: HPMCP-50 dissolves at pH 5.0 and lets most of the drug leave before crystals matter, which "presumably mitigates" surface crystallization; it is the one exception to the trend of poorer release after pH 5.0 than after pH 3.0 C54·C53. Third, polymer dissolution after the shift: HPMCAS-MF and -HF dissolve poorly even at pH 6.5, which "can be attributed" part of their failure, because the ASD remains available for matrix crystallization during the intestinal stage C56.

For HPMCP-55 at pH 1.6, where little drug left in acid although the polymer did not dissolve, the authors turn to the drug's chemical potential in the ASD: when the polymer is insoluble, release should be largest for weakly interacting, poorly miscible systems and smallest for strongly interacting ones (refs 6, 26, 71) C41. They infer that HPMCP-55, with more phthalyl groups, a higher molecular weight and more acid resistance, "may form relatively stronger/more extensive interactions with the drug" C42. No interaction measurement was made to test this.

What it implies for formulation and testing

The authors draw two practical messages. Gastric pH variations, from inter- and intra-subject variability, age, prandial state or acid-reducing agents, should be evaluated for ASDs of weakly basic drugs with enteric polymers, because in vitro testing is usually standardized and such variations "may be important in vivo" for how much drug is absorbed C5·C57. And for a drug that crystallizes under gastrointestinal conditions, "it may be important to minimize contact of the drug with low pH conditions", for example with an enteric coating; formulation strategies against crystallization where the polymer is insoluble "clearly need to be explored" C61·C58. More broadly, they argue that for metastable formulations it is essential to study the phase transitions during dissolution, not only release kinetics C32.

Note by the AI writer (not discussed in the paper). Table B shows why a single pH 6.5 test would have misled: it rates HPMCP-50, HPMCP-55 and HPMCAS-LF alike (about 88–96%), whereas after acid exposure their final release ranges from about 12.5% to 101% depending on the gastric pH R11. For delamanid, only the salt with HPMCP-50 kept final release at or above about 40% after every acid stage tested R11.a–d.

Limitations

Limits stated by the authors. The crystal mass formed during gastric immersion was too low for PXRD, and "due to the low mass of crystals formed, we were unable to investigate quantitative relationships" between crystallization and release; only general trends could be noted C47. The assessment of how surface crystallization varies with pH was "by necessity qualitative", release was "typically (but not always)" lower after pH 5.0 than after pH 3.0, and "ideally, more sensitive methods" would quantify crystallinity C53·C55.

The AI writer's own judgement (1): how far the crystal evidence goes. The causal claim is stated with rising strength, from "was attributed to" in the abstract to "was demonstrated to be responsible" in the conclusions C3. The evidence is a co-occurrence of crystals seen by SEM and PLM on separately prepared films and powders with poor release in the tablets; no crystallinity was quantified, PXRD found none, and the crystals on the ASDs were never identified as free base, an identity the salt argument relies on X10·X11. Two summary statements are wider than the data: the "only 20–65%" final release attributed to ASDs with surface crystals, against observed values from about 0% to 82% after pH 3.0 and 5.0, and lower release after pH 5.0 than after pH 3.0, which holds for HPMCP-55 and the free base but not for HPMCAS-LF and only marginally for MF and HF X5·X6. The HPMCAS-LF and -MF ASDs failed after pH 1.6 (about 47.5% and 40%) although no crystals are reported on their films at that pH, so the pH 1.6 correlation holds only for HPMCP and HPMCAS-HF X7. Equally, the statement that a notable amount of drug was released at pH 1.6 "for all ASDs" excludes HPMCP-55, which released under 10% X4.

The AI writer's own judgement (2): comparisons and conditions. The salt versus free base comparison uses one polymer, and the two materials differ in process and particle size as well as drug form (spray dried versus rotary evaporated, milled and sieved), so the salt advantage is shown for HPMCP-50 under confounded conditions X8. The drug-loading basis and acid:drug ratio of the salt ASDs are not stated, so the polymer mass per tablet is uncertain X12. Figure 2A gives release in µg/mL and Figures 3 and 4 in %; the acid stage used 45–48 mL rather than 50 mL, the basis of the percentage is not stated, and replicate numbers are not given for release, solubility or SR X13. The polymer solubility values above about 3.3 mg/mL are impossible with the stated amounts, and the dashed SR = 1 reference line in Figure 9 is drawn at about 0.8 X1·X15. Finally, the study covers one drug at one loading, a 60 min acid stage and simple HCl and phosphate media without bile salts or food components, although the motivation is partly the fed state.

Conclusion

The paper shows, with a full matrix of five enteric polymers, two drug forms and three gastric pH values, that the release of delamanid ASDs after transfer to intestinal pH depends strongly on what happened in the acid stage C59·R11·R7. The drug dissolves in acid and the polymers do not, which opens a window in which the undissolved ASD can crystallize at its surface; crystallization in the solution was ruled out by a PVPVA control and by the absence of a link between acid-stage supersaturation and final release R1·R4·R22·C37·C39. HPMCP ASDs, and especially HPMCP-50 with the edisylate salt, tolerated the acid best, while the HPMCAS grades crystallized more and released less C1·C4·C2. The causal role of the surface crystals rests on qualitative microscopy and remains to be quantified C47·X10. For a crystallizing weak base in an enteric polymer, the practical lesson is to test release after acid stages across the plausible range of gastric pH, not at intestinal pH alone C5.