Forming a salt inside the dispersion: how sulfonate salts kept delamanid amorphous and restored its release

Background and motivation

Delamanid (DLM) is a nitro-dihydro-imidazooxazole used against multidrug-resistant tuberculosis. It is a weak base with a reported pKa of 4.3 (a predicted value of 3.99 is also cited) and a log P of 5.67, so it is slightly soluble in acidic gastric fluid and much less soluble once the pH rises above its pKa (Section 1, Table 1). M1·C2 The marketed product, Deltyba, is an amorphous solid dispersion (ASD) of delamanid in the enteric polymer hydroxypropyl methylcellulose phthalate (HPMCP); despite a fairly long half-life it is dosed twice daily and must be taken with food for adequate bioavailability. M26·R30

ASDs raise the apparent solubility of poorly soluble drugs, but crystallization is their main failure mode, and the risk grows with drug loading (DL). Whether a drug crystallizes depends on the molecule, the formulation, the process and storage, and some drugs are simply fast crystallizers. C1·C3 Salt formation is the classic tool for changing a drug's solid-state properties: almost half of the drugs marketed in 2007 were salts, and five mesylate and eight tosylate salts appeared in US FDA approvals between 2015 and 2019. A rule of thumb holds that the acid should have a pKa at least 3 units below that of the base for proton transfer and a stable salt. R29·C4 Less widely appreciated is that a salt "may" also change how readily a drug crystallizes: strong electrostatic interactions between drug and counterion "likely" raise the glass transition temperature (Tg) and lower molecular mobility, and bulky counterions may hinder packing (Towler et al. 2008 and others). C5

Salts between basic drugs and acidic polymers had been reported, but ASDs that contain a separate drug salt were rare; Haser et al. (2018) and Liu et al. (2017) formed meloxicam–meglumine and naproxen–meglumine salts in situ during hot-melt extrusion. C6 The authors therefore asked whether delamanid sulfonate salts, with their expected higher Tg, would resist solid-state crystallization better than the amorphous free base, and whether keeping the salt amorphous inside an ASD would improve release (Section 1, "It was hypothesized"). C7 They made eight sulfonate salts (Figure 1), characterized them, prepared ASDs of the free base and of selected salts with HPMCP or hydroxypropyl methylcellulose acetate succinate (HPMCAS) at several drug loadings, and tested release in a single-stage test at pH 6.5 and in a two-stage test that starts at pH 1.6 and shifts to pH 6.5. A3·A4·A8

Background concepts

Amorphous solubility and drug-rich droplets. An amorphous drug can reach a concentration well above its crystalline solubility, up to its amorphous solubility. Above that level the solution separates into a drug-rich liquid phase dispersed as nanodroplets in a drug-lean aqueous phase (liquid–liquid phase separation). The paper measures amorphous solubility by adding a concentrated drug stock to the medium and watching for the abrupt rise in light scattering that marks the appearance of droplets (Section 2.2). P3 For delamanid the ratio of amorphous to crystalline solubility at pH 6.5 is 0.76/0.018, about 42. R1

Supersaturation and induction time. A solution above the crystalline solubility is supersaturated and will eventually crystallize. The nucleation induction time is the time until crystals are first detected, here by a rise in UV extinction at a non-absorbing wavelength (440 nm). Polymers dissolved in the medium can lengthen it greatly, and can also keep drug-rich droplets from growing or crystallizing. P4·C11

Glass-forming ability and residual crystallinity. Drugs differ in how easily they can be made and kept amorphous. In the classification the paper cites (Van Eerdenbrugh et al. 2010), a Class I compound crystallizes on cooling from the melt even at moderate rates, a sign of poor glass-forming ability. C44 When such a drug is processed into an ASD, some crystals may survive the process; this residual crystallinity can remove the solubility advantage and, for some drugs, seed further crystal growth during release (Hate et al. 2020; Moseson et al. 2020). C55

The free energy gap between amorphous and crystalline drug. The paper relates the solubility advantage of the amorphous form to the free energy difference between the two forms (Section 4.1):

In plain terms: $C_a$ and $C_s$ are the amorphous and crystalline solubilities at temperature $T$, $R$ is the gas constant, and the larger the free energy gap $\Delta G$ between the forms, the larger the solubility ratio. E1 The gap can be estimated from calorimetric data alone with the Hoffman approximation:

In plain terms: $\Delta H_f$ is the enthalpy of fusion and $T_m$ the melting point (here 196.1 °C); the further the temperature lies below the melting point, the larger the gap. The paper combines the two equations to predict the solubility ratio at 37 °C. E2·M1

Single-stage and two-stage dissolution. In the single-stage test a tablet is placed directly in pH 6.5 phosphate buffer. In the two-stage (pH-shift) test it spends 1 h in HCl solution at pH 1.6, then concentrated buffer raises the pH to 6.5. Enteric polymers such as HPMCAS and HPMCP carry acid groups and do not dissolve at pH 1.6, so the two tests can rank formulations differently. P15·P16·C63 The drug offered (5 mg in 50 mL, 100 µg/mL) is about 100 times the amorphous solubility at pH 6.5, so both tests run under strongly non-sink conditions. P15·C16

Methods in detail

The study proceeds in four steps: characterize the drug's crystallization problem, choose a polymer that holds supersaturation, show why free-base ASDs fail, and test whether salts formed in situ fix it.

Step 1: the drug's crystallization problem

Crystalline solubility was measured by shaking excess drug in fasted state simulated gastric fluid (FaSSGF), fasted state simulated intestinal fluid version 1 and 2 (FaSSIF V1, V2) and phosphate buffer solution (PBS) pH 6.5 at 37 °C for 48 h, removing solids by ultracentrifugation and assaying by HPLC. P1·P2 Amorphous solubility was measured in the same media by the UV-extinction method: a DMSO stock was pumped into the medium at 50–100 µL/min, keeping DMSO below 1% v/v, until scattering at 400–450 nm rose abruptly. P3 The induction time without polymer was then measured at a concentration equal to the amorphous solubility, at pH 1.6 and pH 6.5. P4 Glass formation of the neat drug was tested by cooling the melt at up to 50 °C/min and by quenching it in liquid nitrogen (Figures S1 and S9, described in the text). P18

Step 2: choosing the polymer

Two neutral polymers (HPMC, PVPVA) and three weakly acidic ones (Eudragit L100, HPMCP, HPMCAS) were dissolved at 300 µg/mL in PBS pH 6.5, where all five are soluble. The induction time was measured with the drug at its amorphous solubility (0.76 µg/mL), and droplets produced by adding 50 µg/mL drug (from an acetonitrile stock) were sized by dynamic light scattering (DLS) for 3 h. For HPMCAS and HPMCP the droplet size was also measured at 2–100 µg/mL drug; the caption of Figure 2C gives the polymer concentration for that series as 1000 µg/mL, while the methods mention only 300 µg/mL. P4·P7·X17

Step 3: free-base ASDs and the marketed tablet

Free-base ASDs were prepared by dissolving delamanid and HPMCAS (LF grade) or HPMCP (HP-50 grade) in dichloromethane (DCM) and methanol (1:1 v/v), removing the solvent on a rotary evaporator at 40 °C, drying under vacuum overnight, cryo-milling and sieving to 106–250 µm. Drug loadings were 5, 10, 15, 20 and 40% with HPMCAS and 5, 10, 15, 20 and 25% with HPMCP. P8 The dispersions were examined by powder X-ray diffraction (PXRD, 4–40° 2θ), differential scanning calorimetry (DSC; three heat–cool cycles from 0 to 210 °C, the last analysed), ATR-FTIR and dynamic vapour sorption at 37 °C (5–95% RH). P9·P10·P11·P12

Powders floated on the medium, so release was tested on tablets: each ASD was mixed with excipients (the formulation is in Table S1) and compressed to contain 5 mg delamanid as free base. P14·R12 Single stage: the tablet in 50 mL PBS pH 6.5 at 37 °C and 150 rpm. Two stage: 45 mL HCl solution pH 1.6 for 1 h, then 5 mL concentrated PBS (pH 7.3) to reach pH 6.5 for 30 min more. Concentrations were followed in situ by fibre-optic UV, with second-derivative baseline correction and calibration on the area under the 330–350 nm band; all tests were in triplicate. P15·P16 Because release in FaSSIF matched release in buffer (Figure S3), buffer was used throughout. R13·C15 Deltyba tablets were tested the same way; the paper does not state how much Deltyba was put in each vessel, but expresses its release as a percentage of 100 µg/mL. P17·X9

Step 4: salts and in situ salt ASDs

Each sulfonic acid (Figure 1: methane-, ethane-, 1,2-ethanedi-, benzene-, p-toluene-, 4-chlorobenzene-, camphor- and 1,5-naphthalenedisulfonic acid) was dissolved with delamanid at a 1:1 drug-to-acid molar ratio in DCM and acetone (1:1 v/v) and the solvent removed by rotary evaporation at 40 °C. Alcohols were avoided because sulfonic acids esterify with them. P5·C8 The salts were characterized by 1H NMR (to locate the protonation site), IR, PXRD, DSC, water sorption and induction time, then stored in open dishes at 40 °C/75% RH for 2 weeks and re-examined by PXRD, 19F NMR (impurities) and HPLC (drug content). P6·P13 Table 2 names the edisylate and napadisylate as 2:1 salts, and an edisylate (1:1) with excess acid is reported separately, so the stoichiometry of the diacid salts is not fully clear from the methods. X5

The salt ASDs were prepared "in situ": delamanid, the polymer and the acid were dissolved together in DCM and acetone (again avoiding methanol) at a 1:1 drug-to-counterion molar ratio and rotary-evaporated as before. P8 Two details matter for comparing them with the free-base ASDs. The solvent is different (DCM–acetone rather than DCM–methanol), and the paper does not say whether "drug loading" for a salt ASD counts the free base or the whole salt. X7·X6 Water sorption and Tg were measured for 20% DL salt ASDs with HPMCAS; release was tested for DLM-edisylate ASDs at 10–40% DL with both polymers, and for the besylate, edisylate, mesylate and tosylate ASDs at 25% DL with HPMCP. A6·A7

Experimental analysis

The drug: a fast crystallizer with steep pH dependence

Table A collects the baseline data. Amorphous solubility falls about 90-fold from FaSSGF (69.9 µg/mL) to PBS pH 6.5 (0.76 µg/mL); the two FaSSIF media sit in between, which the authors take as "indicating" solubilization in bile salt/lecithin micelles. R1·C9 At a concentration equal to the amorphous solubility, crystals appeared after 2.4 min at pH 1.6 and 10.7 min at pH 6.5. R2 The amorphous drug has a Tg of only 43.3 °C, could not be made by cooling the melt at 50 °C/min, and a glass made by quenching in liquid nitrogen recrystallized on heating just above Tg; the authors class delamanid as a poor glass former (Class I). M1·R3·C10·C44

Table A. Delamanid solubility and induction time at 37 °C (from Table 1; ratios computed by the AI writer from the table). R1·R2·X2

The Hoffman estimate gives an amorphous-to-crystalline solubility ratio of 31.8 at 37 °C, which the authors call in "reasonable agreement" with the experimental 42.3. R27·C43 Note by the AI writer (not discussed in the paper): the text cites Table 2 for the 42.3, but the solubilities are in Table 1, and 42.3 is the pH 6.5 ratio; in the other media the measured ratio is 4.0 to 36.2, so the agreement depends on choosing the buffer value. The enthalpy of fusion used is only in Figure S1, so the 31.8 cannot be recomputed from the main text. X2·E2

The polymer screen

Without polymer, droplets formed at 50 µg/mL crystallized immediately. R7 With 300 µg/mL polymer, PVPVA, HPMCP and HPMCAS prevented crystallization for the whole 1000 min observed, HPMC delayed it to about 50 min, and Eudragit L100 did nothing (10.2 ± 3.1 min). R4·C12 Droplet size (Figure 2B) separated the three effective polymers: with HPMCP the droplets stayed at about 440 nm and with HPMCAS at about 600 nm for 3 h, whereas with PVPVA they grew from about 455 to about 900 nm (the authors say the droplets "ripened"). In HPMC and Eudragit L100 the scattering species grew to micrometres within 30–60 min as crystals formed. R5·C13 With HPMCAS or HPMCP the droplets measured about 505–660 nm across 2–100 µg/mL drug. R6 HPMCP and HPMCAS were chosen for the ASDs; in the discussion the authors argue that, because drug-rich nanodroplets "are thought to" aid absorption and their size "may play a role", PVPVA "shows disadvantages". C13·C52

Table B. Polymer screen at pH 6.5 and 37 °C (Figure 2A and text; droplet sizes read from Figure 2B, approximate). R4·R5·R7

Free-base ASDs: crystals and collapse

Rotary evaporation could not keep the free base amorphous above about 10–15% DL. PXRD (Figure 3A) shows a weak drug peak at 15% DL with HPMCAS and clear drug peaks at 20 and 40%; with HPMCP, weak features at 20% DL and clear peaks at 25%. R8 Tg fell steadily with drug loading (Figure 3B) because delamanid, with its Tg of 43.3 °C, plasticizes polymers whose Tg is about 120 °C; the 40% DL HPMCAS dispersion also showed a recrystallization exotherm near 127 °C and melting near 182 °C on heating. R9·C14 Water uptake at 95% RH fell from about 11–12% for the neat polymers to about 8% at 20% DL, and crystalline delamanid took up almost none. IR showed no specific drug–polymer interaction (Figure S2). R10·R11

Table C. Free-base ASDs: PXRD (Figure 3A), Tg printed on the DSC traces (Figure 3B) and release end values read from Figure 4 (approximate); 100 µg/mL is complete release. R8·R9·R14

Release followed the crystallinity. At 10% DL both dispersions released rapidly (plateau within 5–10 min) and held the supersaturation, reaching about 92 (HPMCAS) and about 98–100 µg/mL (HPMCP) at pH 6.5; at 20% DL release dropped to about 6 and 53, and at 25% to about 2 and 20 µg/mL. R14·C18·C21 The authors describe the 10% DL release as complete for both polymers, but the HPMCAS curve plateaus near 92 µg/mL. X15 Their explanation is that the crystals present in the ASD "presumably" grew in the hydrated matrix or in solution and pulled the concentration down; later they say the poor release "can be explained" by growth of these crystals competing with dissolution of the surrounding amorphous drug, and that the low release "indicates" that the polymers cannot substantially delay crystal growth under hydrated conditions. C19·C56·C57 Crystal growth during release was not measured. Note by the AI writer: PXRD and release were run at only partly overlapping loadings (no PXRD for the 25% DL HPMCAS dispersion, no release for the 15% DL ones), so the link "detectable crystals, incomplete release" rests on the 20% DL HPMCAS and 20–25% DL HPMCP dispersions. X16

In the pH-shift test the free-base dispersions ended higher than at pH 6.5 alone: at 20% DL, about 35 (HPMCAS) and 87 µg/mL (HPMCP); at 25% DL, about 30 and 55. R14 Crystalline delamanid reached about 20 µg/mL after the shift, which the authors attribute to its higher solubility at low pH. C17 The marketed tablet behaved like the 25% DL free-base HPMCP dispersion (Figure 5): about 20 µg/mL at pH 6.5, about 45 µg/mL at the end of the acid stage and about 60 µg/mL after the shift. R15·C22 The authors write that this "may indicate a similar failure mechanism" for Deltyba, which "would require further investigation". C60

The salts: amorphous, high Tg, but hygroscopic

Salt formation was confirmed at the piperidine nitrogen. In the 1H NMR spectrum of DLM-edisylate the piperidine protons shifted downfield while the protons near the imidazole ring hardly moved (Figure S4), and the IR spectra of the salts showed a broad, intense band at 2770–2380 cm⁻¹ (maximum 2519 cm⁻¹) assigned to the tertiary N⁺–H stretch, while a free-base band at 2816 cm⁻¹ disappeared (Figure S5). R16·R17·C23·C24 Seven of the eight salts were amorphous as made; the napadisylate was partly crystalline (Figure 6A). R18·C25 Note by the AI writer: the napadisylate peaks lie at positions of the crystalline free-base pattern, and the paper does not identify the crystalline phase, so incomplete salt formation is not excluded. X14

Table D. Delamanid sulfonate salts (from Table 2); stability after 2 weeks at 40 °C/75% RH in open dishes, when all seven amorphous salts were still amorphous. For comparison, the free base has Tg 43.3 °C and induction times of 2.4 and 10.7 min. R20·M1·R2

Every amorphous salt had a Tg far above that of the free base, from 83.7 °C (esylate) to 117.8 °C (edisylate 2:1), and all seven stayed amorphous for 2 weeks at 40 °C/75% RH; the authors call this stability "remarkable". R20·C31·C47 Excess acid undoes part of the gain: the edisylate (1:1) had a Tg of only 53.9 °C and took up 59% water at 95% RH. R21·C29 Induction times from solution were close to those of the free base, "as expected" in the authors' words. R20·C30 Note by the AI writer: the text gives "around 2 min" in FaSSGF, but Table 2 lists 0.6–1.3 min. X12

The price is water. All salts took up more water than the free base, from 5.8% (closylate) to 21.1% (mesylate) at 95% RH; the aromatic salts took up the least, which the authors say "can be attributed" to their more lipophilic counterions. R20·C26·C28 Four salts (besylate, esylate, mesylate, tosylate) liquefied during storage, "presumably" through plasticization by water. R20·C27 Chemically, 19F NMR found 0.3–2.3% impurities and drug content fell by up to 6.1%, most for the closylate and camsylate. R20 The besylate, edisylate (2:1), mesylate and tosylate were chosen for ASDs. C33 Note by the AI writer: the text lists the closylate among the liquefied salts, while Table 2 marks it "–" and the inset photograph of Figure 6B shows a granular sample; the text also names only four salts as showing impurities, while Table 2 gives non-zero impurity for all seven and a 2.8% drug content loss for the mesylate. X1·X11 Three of the four selected salts liquefied, so the abstract's "good chemical and physical stability" holds in the sense of staying amorphous. X19

Salt ASDs: higher Tg, more water

At 20% DL with HPMCAS, the salt dispersions had Tg values of 100.4 (tosylate), 101.9 (besylate), 102.1 (mesylate) and 117.0 °C (edisylate), against 86.7 °C for the free-base dispersion, the edisylate mirroring the high Tg of its neat salt. R23·C35 They also took up more water at 95% RH: about 10–14% against about 8% (Figure 7A). R22·C34 No PXRD of any salt dispersion is shown in the main text. X8

Release from DLM-edisylate ASDs

Neat DLM-edisylate released nothing at pH 6.5 and about 28 µg/mL in the acid stage, slightly more than the crystalline free base but below the amorphous solubility measured in FaSSGF. R24·C36 Dispersed in a polymer, the edisylate released far more (Table E). R24

Table E. Release from DLM-edisylate ASDs, µg/mL of a possible 100 (read from Figure 8, approximate). R24

At pH 6.5 alone, HPMCAS dispersions released "nearly complete[ly]" from 10 to 30% DL and HPMCP dispersions up to 25% DL, beyond which HPMCP release fell steeply (about 59 at 30% and 21 at 40% DL). R24·C37 After the acid stage the order reversed: HPMCP dispersions still released about 98–100 µg/mL up to 25% DL, whereas only the 10% DL HPMCAS dispersion released almost completely. R24·C38 The authors state that HPMCAS dispersions released more in the acid stage than HPMCP ones; in Figure 8B this holds at 10 and 20% DL but not at 25–40%. C38·X3 The salt dispersions also produced stable drug-rich nanodroplets during release, smaller with HPMCP than with HPMCAS (Figure S8). R25·C39

The authors describe release as enhanced relative to the free-base ASDs for 10–40% DL. C37 Note by the AI writer: at 10% DL the free-base dispersions released equally well (about 92–100 µg/mL), and free-base dispersions at 30–40% DL were not tested, so the improvement is shown at 20 and 25% DL. The drop at 30–40% DL with HPMCP is not discussed in the paper. X18·X8

Four salts at 25% drug loading

Figure 9 compares the four selected salts with the free base, all at 25% DL with HPMCP (Table F). At pH 6.5 every salt dispersion released about 95–97 µg/mL against about 20 for the free base; after the pH shift they reached about 85–91 against about 55. In the acid stage the concentrations ranged from about 19.5 (tosylate) to about 32 µg/mL (edisylate). R26·C40 The abstract calls this a "remarkable improvement". C62

Table F. Release at 25% DL with HPMCP, µg/mL (read from Figure 9, approximate). R26

Note by the AI writer: the same 25% DL edisylate–HPMCP dispersion ends at about 100 µg/mL after the shift in Figure 8B but at about 89 µg/mL in Figure 9B, with similar acid-stage values; the paper does not say whether these are separate runs. X4

Discussion

The authors' chain of reasoning

The paper's argument links the drug's poor glass-forming ability to the process, the process to residual crystals, and the crystals to release; the salt breaks the chain at the second link.

Two parts of this chain are inferred rather than measured. The growth of residual crystals during release was not followed (no PXRD of tablets after dissolution, no crystal growth rates), and the absence of crystals in the salt dispersions at 25–40% DL is stated in the discussion ("highly successful in enabling higher DL ASDs to be prepared with no detectable residual crystallinity") without data shown in the main text. C56·C48·X8 The authors place delamanid among drugs whose trace crystallinity strongly reduces release (tacrolimus, bicalutamide), unlike indomethacin, whose residual crystals were poisoned by the ASD polymer. C58

Why salts might resist crystallization

The paper offers two reasons. The first, the hypothesis behind the study, is the higher Tg: electrostatic interactions between the protonated drug and the counterion "likely" raise Tg and lower molecular mobility. C5·C7 The measured Tg values support that the salts are far less mobile at storage temperature, but mobility itself was not measured. R20 The second is structural: counterions can disrupt a crystal lattice as well as stabilize one, depending on the counterion and the site of ionization, and the authors "speculate" that protonating the piperidine ring keeps the long, thin delamanid molecules from lining up. No single-crystal structure of delamanid is available to test this. C49·C50

Polymer choice and the pH-shift test

HPMCP "generally" outperformed HPMCAS, both for the free base (about 53 against 6 µg/mL at 20% DL) and for the edisylate after a pH shift. C21·C62·R14·R24 The ranking is not universal: at pH 6.5 alone the edisylate–HPMCAS dispersions released more than the HPMCP ones at 30 and 40% DL. R24 The acid stage also changed outcomes in opposite directions. Free-base dispersions released more after an acid stage than at pH 6.5 alone, while several salt dispersions released less; the authors suggest that, because the enteric polymers do not dissolve at pH 1.6, the drug left in the matrix during the acid stage "may" become physically unstable. R14·R24·R26·C63 From this they draw two practical points: ASDs with enteric polymers and ionizable drugs should be tested under biorelevant conditions, at least with pH changes, and the effect of gastric pH variation (fed or fasted state, age, acid-reducing drugs) needs further study. C65·C64

What it suggests for formulation

Stated by the authors: combining salt formation with ASD formation "is a promising approach" to alter crystallization tendency and improve release of poorly soluble compounds that are hard to formulate with a single enabling strategy; faster solvent removal such as spray drying "is likely" to give crystal-free free-base ASDs at higher loading; and sulfonate salts should be made without alcohols to avoid ester formation. C67·C46·C8

Note by the AI writer (not discussed in the paper): the salt screen in Table 2 shows that the choice of counterion is a trade-off. The highest-Tg salt (edisylate 2:1) took up 11.6% water at 95% RH against 5.8–7.1% for the aromatic salts, three of the four salts carried into ASDs liquefied at 40 °C/75% RH, and excess acid lowered the edisylate Tg from 117.8 to 53.9 °C. A salt ASD therefore needs its own storage study. The marketed spray-dried product still released only about 60% after a pH shift, so a faster process alone may not reach the release of the salt dispersions, although the paper did not test the free base by spray drying. R20·R21·R15

Limitations

Stated by the authors. The cause of Deltyba's incomplete release "would require further investigation"; the effect of gastric pH variation should be studied further; and no single-crystal structure of delamanid is available to support the packing argument. C60·C64·C50

The AI writer's own judgement. The release contrast is large and was measured in triplicate with four different salts, and the free-base crystallinity is visible by PXRD, so the core observation (salt ASDs at 25% DL release far more than free-base ASDs) is solid. R26·R8 The weaker points are these:

• No PXRD of any salt dispersion and no storage data for salt dispersions appear in the main text; the claims that they were crystal-free and stable "during preparation and storage" cannot be checked here, and the Supporting Information was not available. X8
• Free-base and salt dispersions were cast from different solvents (DCM–methanol and DCM–acetone), and the drug-loading basis of the salt dispersions is not stated, so part of the difference could come from the process or from the polymer content. X7·X6
• Crystallinity was never quantified, and the loadings tested by PXRD and by release overlap only in part. X10·X16
• Several statements in the text differ from the tables or figures: the closylate liquefaction, which salts showed impurities, the salt induction times in FaSSGF, the acid-stage ranking of HPMCAS and HPMCP, the table cited for the solubility ratio, and the end value of the 25% DL edisylate–HPMCP dispersion in Figures 8B and 9B. X1·X11·X12·X3·X2·X4
• The Deltyba dose per vessel is not printed, so its percentage release depends on an assumed 5 mg. X9
• One drug, one process and in vitro release only; no absorption or bioavailability data. C67

Conclusion

For delamanid, a weak base that crystallizes within minutes and cannot be vitrified from the melt, rotary-evaporated ASDs with HPMCAS or HPMCP held crystals from 15–20% drug loading, and their release collapsed from about 92–100 µg/mL at 10% DL to about 2–53 µg/mL at 20–25% DL. R8·R14 Sulfonate salts raised Tg from 43.3 °C to 83.7–117.8 °C and stayed amorphous for 2 weeks at 40 °C/75% RH, at the cost of more water uptake and, for four salts, liquefaction. R20·M1 Formed in situ during ASD preparation, the besylate, edisylate, mesylate and tosylate salts gave HPMCP dispersions at 25% DL that released about 95–97 µg/mL at pH 6.5 and about 85–91 after a pH shift, against about 20 and 55 for the free base. R26 The authors conclude that the dual strategy "is a promising approach"; the crystal-free state of the salt dispersions and the crystal-growth mechanism remain to be shown directly. C67·X8