When humid PEO dissolves the crystalline drug it carries

Background and motivation

Poly(ethylene glycol) (PEG) and its high-molecular-weight form, poly(ethylene oxide) (PEO), are workhorse excipients. They serve as cosolvents, as carriers in solid dispersions, as the matrix of controlled- and sustained-release tablets, and, chemically modified, in hydrogels, micelles and liposomes (refs 1–23 of the paper). To understand any of these dosage forms one has to know how many phases are present and how stable each of them is (Craig 1990, ref 13). C1 PEO makes this harder than a fully amorphous polymer would, because it is semicrystalline: both the polymer and the drug can exist as crystal or as amorphous material, and each can change the phase stability of the other. C1 Melting PEO together with a crystalline drug can change PEO's amorphous fraction on cooling and produce an amorphous molecular mixture from which either component may later crystallize, and PEO's own crystal packing and amorphous fraction depend on its thermal history (refs 8, 13, 24–30). C2 The number of phases may also change with temperature or on exposure to water vapour, which matters for shelf life. C3

The study that frames this paper is Schachter et al. (2004, ref 31). They heated physical mixtures of ketoprofen and PEO at 1 °C/min and saw the ketoprofen X-ray diffraction peaks lose intensity at 51 °C, well below the melting point of PEO, while the PEO peaks remained; 13C solid-state NMR showed part of the ketoprofen dispersing into amorphous PEO at 43 °C, and 1H NMR linewidths narrowed below the PEO melting point. R19 They "speculated" that the "dissolved" ketoprofen sits in the amorphous regions of PEO, and the present authors take from it that a second component can render a seemingly stable crystal disordered. C4 In other words, a crystal that is stable on its own may not be stable once it touches the disordered part of a semicrystalline polymer.

Water is the second stress. Many pharmaceutical polymers are hygroscopic. The Taylor group had shown that anhydrous drugs form hydrates in the presence of poly(vinylpyrrolidone) K12 at high RH, a change suggested to be solution-mediated and to follow partial dissolution of the drug (Salameh and Taylor 2006, ref 32). C5 Water can also change the polymer itself: in semicrystalline poly(vinyl alcohol) films, diffusing water destroyed crystalline regions at the amorphous/crystalline interface (Hodge et al. 1996, ref 33). C6 PEO sorbs large amounts of water, most of it in the amorphous regions, and the authors find it "conceivable" that this alters the polymer and lowers the crystallinity of a drug held in it. C7 Such a loss matters in practice: amorphous materials most often degrade faster, often dissolve faster, and a change of physical form could change the bioavailability of a dissolution-rate-limited drug (refs 34–38). C8

The paper therefore reports a case in which initially crystalline drugs, compacted as physical mixtures with PEO, lose crystallinity when stored at high RH, and asks two questions: which properties of the drug and of the polymer lead to the transformation, and by what mechanism. A1·A2 The authors expected that the extent of loss "could be rationalized" by moisture-induced changes in the structure of the polymer and by the physicochemical properties of the drugs. C38

Background concepts

A semicrystalline polymer has two parts. PEO consists of ordered crystalline lamellae with disordered (amorphous) chain segments between them. Only the disordered part can take up water or dissolve a drug; the authors presume that the crystalline fraction "cannot serve as a solvent" for the drug (Craig 1990, ref 13). C20 How much of PEO is disordered therefore sets how much drug it could dissolve. Literature values for the crystalline fraction of PEO are 76–90% from true density for molecular weights of 1000 to 3,000,000, and up to 95 wt% from NMR (refs 43, 44). M7 The authors estimate the crystallinity of their own PEO from its enthalpy of fusion, 197 J/g, against 216 J/g for perfectly crystalline PEO (Afifi-Effat and Hay, ref 45): M7·R15

In plain terms: the PEO melts with 91% of the heat a fully crystalline sample would need, so it is about 91% crystalline and about 9% amorphous. E3·R15 The text of the paper calls the 91% the "estimated amorphous fraction", but the calculation it then performs (Table 3, footnote a) uses "9% amorphous", and only the 9% value reproduces Table 3; the 91% in the text is the crystalline fraction. X1·E4

Deliquescence. Above a critical relative humidity, called RH₀, a crystalline solid begins to dissolve in the film of water condensed on its surface (Zografi 1988, ref 49; Salameh and Taylor 2005, ref 50). The solution that forms has a lower water activity than the surrounding air, so it draws in more water, which dissolves more crystal, and the process continues until all of the crystal has dissolved and the solution reaches the aqueous solubility of the crystal. C30 For PEO, Olsen et al. (2006, ref 51) reported an equilibrium deliquescence point at a water activity of 0.93 at 20 °C, that is, about 93% RH; they related it to the low melting point and high aqueous solubility of PEO, found that water sorbed into the material between the lamellae destabilizes them, and noted that both the thermodynamics and the kinetics depend on the polymer's history and that the transition is not sharp. R22 The 94% RH used in this paper lies just above that point. P2·R22

Ideal solubility and activity coefficient. The ideal solubility of a crystal is the mole fraction it would reach in a solvent with which it mixes ideally; it depends only on the crystal's melting temperature and enthalpy of fusion. The paper tabulates it as S^ideal but does not print the relation it used or its temperature. E1·X5 The activity coefficient γ compares ideal and real solubility; the paper does not print the relation, but a check by the AI writer shows that the printed values equal S^ideal divided by the measured or cited solubility, within rounding for most drugs. E2·X5 A coefficient below 1 means the drug dissolves better than ideal; one far above 1 means it dissolves much worse. If the entropy of mixing is close to ideal, the authors read γ below 1 as exothermic mixing and γ above 1 as endothermic mixing. C14

Plasticization and molecular mobility. A plasticizer lowers the glass transition temperature (T_g) of an amorphous phase and so raises its molecular mobility and lowers its viscosity; an anti-plasticizer does the opposite. Pure amorphous PEO has a T_g of about −67 °C (reported −67 to −55 °C, and up to −20 °C when crystalline regions are present; refs 46, 47), and water has a T_g of −136 °C (ref 48). M7·M12 Water therefore plasticizes the amorphous PEO, while the drugs, whose T_g values lie between −43.6 and 44.4 °C, would, once dissolved, "most likely anti-plasticize" it. C26·C27·M1·M2·M3·M4·M5·M6

The T_g/T_m rule. For naproxen, whose amorphous form "is not isolated easily", the T_g in Table 1 is an estimate from the melting point using the empirical ratio (Table 1, footnote a, after ref 53): M3·E5

In plain terms: the glass transition, in kelvin, is taken as 70% of the melting point. E5 Applied to the Table 1 melting point of naproxen (155.21 °C, or 428.36 K) the rule gives 26.7 °C rather than the printed 24 °C; the paper does not say which melting point ref 53 used, so the naproxen T_g is best read as about 24–27 °C. E5·X4

Methods in detail

The study has a simple design: one polymer, one drug loading, one high humidity, six drugs. Its contributions are four kinds of measurement on the same compacts and two kinds of calculation that turn the drugs' properties into numbers that can be ranked against the outcome. A1·A2·A3·A4·A5·A6 The flow below summarizes it.

Contribution 1: compacts that put drug crystals in contact with PEO

Problem. To see whether PEO can dissolve a crystalline drug at room temperature, the drug crystals must touch the polymer, but must not be melted with it, because comelting would itself create amorphous mixtures. C2·C16

What they did. The six drugs were chosen to span molecular weight, melting point, aqueous solubility and log p: acetaminophen, ketoprofen, naproxen, ibuprofen, felodipine and ketoconazole (Figure 1). A1·M1·M2·M3·M4·M5·M6 The polymer was Polyox WSR N-10, average M_w about 100,000 ("PEO 100000"), dried over phosphorus pentoxide for at least a week. M7 Drug and PEO were sieved to a 45–75 µm fraction, mixed geometrically into 500 mg physical mixtures containing 10 wt% drug, and pressed in a 16 mm die at 2040 psi with a 1 s dwell. P1 Compacts were stored at 0% RH and at 94% RH; the 94% RH desiccator held a saturated potassium nitrate solution, at 22 °C according to the moisture-uptake section. P2 Acetaminophen compacts were also stored at 75% RH. R3 The storage temperature of the compacts used for spectroscopy is not stated separately, and the dry controls are described at 25 °C. X6

Why it works. Compaction of fine particles gives close contact along the particle–particle interfaces, where crystalline drug meets PEO's amorphous regions; the authors hypothesize that the drug can be dissolved by PEO at these contacts. C16 Each compact holds 50 mg of drug and 450 mg of PEO, so the drug is always the minor component. E4

Figure 1 has two drawing problems that do not affect the experiments: it includes nifedipine (panel b), which is not studied anywhere in the paper, and its acetaminophen structure (panel d) carries an N-methyl group that acetaminophen does not have. X2·X3

Contribution 2: two independent probes of drug crystallinity

Problem. At 10 wt% drug, the diffraction pattern of a compact is dominated by PEO, and a drug that loses crystallinity has no simple amorphous reference spectrum. R9·R1

What they did. FT-Raman spectra were taken at 1064 nm excitation, 1000 mW, 4 cm⁻¹ resolution (1.0 cm⁻¹ data interval) and at least 256 accumulations, with the compact rotated by a motor to sample more volume and avoid heating. P3 Each compact was compared with the crystalline drug and with the drug dissolved at its solubility limit in PEG 400, held in a glass vial. P3 The PEG 400 solution served as the reference for dissolved, non-crystalline drug because pure amorphous acetaminophen, naproxen and ibuprofen crystallized very readily on cooling (data not shown); for ketoconazole, whose PEG 400 solution gave a weak signal, the amorphous drug was the reference. R1 The authors state that the PEG 400 spectra are "sufficiently similar" to amorphous spectra for a qualitative assessment. C9 X-ray powder diffraction (XRPD) used Cu Kα radiation (1.5406 Å) with polycapillary optics over 5–35° 2θ; for each drug the compacts were compared with pure crystalline PEO and pure crystalline drug, and strong drug peaks clear of the PEO peaks were marked with arrows (Figure 4). P4·R10 Raman spectra were taken at up to six times between 0 and 28 days; XRPD at 0, 6 and 17 days for acetaminophen and at 0 and 28 days for the others. P2

Why it works. The two probes look at different things. Raman follows a vibrational band of the drug and shows whether it moves from the crystal position toward the dissolved position and broadens; XRPD shows whether long-range crystalline order remains, both for the drug and for PEO. R2·R9·R10 Agreement between them makes a qualitative grade more credible than either alone. C10

Contribution 3: following the water

What they did. Whole compacts were weighed during storage at 94% RH (22 °C) over saturated potassium nitrate, and the water uptake after 28 days was reported as weight fraction on a dry basis (Figure 6). P6·R13 Pure PEO was equilibrated at a series of RH values for several hours and for 5 months (Figure 5); the paper gives no instrument, temperature or sample form for this isotherm. P7·X6 The pure drugs were also weighed at 94% RH (data not shown). R12

Why it matters. If water drives the loss of crystallinity, the amount and the timing of water uptake by PEO are part of the mechanism; a very slow uptake would point to a slow change in the polymer itself rather than simple surface sorption. C29·C30 Note that the text gives these water contents as "wt.%", whereas Figure 6 is labelled "dry basis"; the numbers (about 20 and 45 wt%) match the dry-basis fractions (about 0.2 and 0.46), so they are grams of water per 100 g of dry compact. X15

Contribution 4: thermodynamic yardsticks for the drugs

Problem. The authors want to know whether the outcome can be predicted from properties of the drug. The obvious candidate, the drug's solubility in amorphous PEO, cannot be measured: dry and at room temperature the transformation is too slow to reach equilibrium in a reasonable time. C18

What they did. The melting temperature and enthalpy of fusion of each drug were measured by DSC at 10 °C/min in pin-holed aluminium pans under 45 mL/min nitrogen; the T_g was measured for acetaminophen (22.1 °C) and cited for the others (Table 1). P8·M1·M2·M3·M4·M5·M6 As a stand-in for amorphous PEO, solubility was measured in PEG 400, its liquid low-molecular-weight analogue: excess drug was stirred in PEG 400 for at least 24 h at 25 °C, filtered through 0.2 µm, diluted in ethanol and read by UV against five-point calibrations (R² > 0.99). P5 Aqueous solubilities were taken from the literature (refs 57–59; the felodipine value carries no reference), and the ideal solubility and the activity coefficients in PEG 400 and in water were tabulated (Table 2). P9·R14·X16

The authors discuss why PEG 400 is an imperfect stand-in. PEG 400 has more hydroxyl end groups than PEO, which should make PEO the better solvent for these relatively nonpolar drugs (acetaminophen excepted); mixing with the much longer PEO chains gains less entropy, which should make PEO the worse solvent. C19 Their own observation that indomethacin is more soluble in PEG 400 than in PEG 200 (data not shown), and literature showing the same for diazepam but equal solubility for benzocaine and phenytoin (refs 40–42), lead them only to the cautious statement that relatively nonpolar drugs "generally" appear more soluble as PEG molecular weight rises; the true answer "remains elusive". R18·R20·R21·C19

With the PEG 400 solubility as a proxy, the amount of drug that the amorphous part of the PEO in one compact could dissolve, without any water, follows from Table 3, footnote a: E4·P10

In plain terms: take the 9% of the 450 mg of PEO that is amorphous (40.5 mg), turn it into a volume with the density of amorphous PEO, ρ = 1.126 g/cm³, and fill that volume with drug at its PEG 400 solubility S^{PEG 400}; Table 3 reports the result as a percent of the 50 mg of drug in the compact. E4·M7·R16 The paper prints only mole-fraction solubilities; converting the ketoprofen value (0.32) to mass with a molar mass of 400 g/mol for PEG 400 gives about 0.30 g drug per g solvent and reproduces the 24% in Table 3, a check by the AI writer. E4·R14.b·R16.b

Experimental analysis

Main result 1: three outcomes in the same matrix. The Raman spectra (Figure 2) separate the six drugs into three groups. R2·R4·R5·R6·R7·C10 Table A collects the band positions the paper gives.

Table A. Raman band positions (cm⁻¹) of the six drugs, from the text describing Figure 2; positions marked "near" are read from the figure (approximate). R2·R4·R5·R6·R7·C10

Acetaminophen is the clear case: the crystalline bands at 1610 and 1648 cm⁻¹ shrink over 1, 2 and 7 days while the dissolved-state bands at 1619 and 1661 cm⁻¹ grow, and after 14 days the spectrum shows no crystalline acetaminophen. R2 Its diffraction tells the same story: the drug peaks at 15.5, 18.2, 20.4, 24.3 and 26.6° 2θ show little if any sign after 6 days, and after 17 days the pattern is a completely X-ray amorphous halo (Figure 4a). R10 Acetaminophen compacts stored at 75% RH also lost crystallinity "significantly", though less than at 94% RH (data not shown). R3 For ketoprofen, naproxen and ibuprofen the Raman band moves only 1–2 cm⁻¹ toward the PEG 400 position, and broadens; in XRPD the ketoprofen peaks (14.4, 18.4, 29.6, 30.5° 2θ) leave little sign after storage, the naproxen peaks (12.9, 17.4, 20.5° 2θ) give a very poor signal, and the two strong ibuprofen peaks (16.7 and 20.12° 2θ) "may" partly remain. R4·R5·R6·R10 Felodipine and ketoconazole spectra after 28 days look like the crystal, and several of their diffraction peaks persist. R7·R10 The authors summarize: "it appears" that acetaminophen loses its crystallinity completely, ketoprofen, naproxen and ibuprofen significantly but incompletely, and felodipine and ketoconazole "little if any". C10

Controls. Compacts stored at 0% RH showed no change, and the pure crystalline drugs kept their crystallinity at 94% RH without PEO; the pure drugs also took up only minimal water at 94% RH, which the authors read as surface adsorption only. R8·R12·C11 Both controls are stated in the text, with the data not shown. X7 Taken at face value they make the effect depend on both water and PEO: neither alone changes the drug. C36

Main result 2: PEO itself changes. In the full diffractograms (Figure 3) the two main PEO peaks, at 19.2 and 23.4° 2θ, dominate. R9 After storage at 94% RH, the compacts containing ketoprofen, naproxen, ibuprofen, felodipine and ketoconazole show a decrease in intensity of these two peaks (described as "dramatic") and a shift to slightly higher angles; in the acetaminophen compact they are absent after 17 days, and the compact has become a gelatinous mass. R9 Later in the discussion the authors describe the same patterns as a reduction in intensity and a clear broadening of the PEO peaks, which they take as a loss of crystallinity of the polymer. R9·C31 The compacts also lost mechanical integrity in the same order: acetaminophen compacts became gelatinous after only a few days, ketoprofen, naproxen and ibuprofen compacts noticeably softer, and felodipine and ketoconazole compacts slightly weaker. R17·C32

Table B. Water sorption of PEO 100000 at the upper end of the isotherm, read from Figure 5 (approximate); below about 65% RH both series stay under about 1%. R11

The isotherm explains why the authors speak of a slow process (Table B). Pure PEO takes up little water below about 65% RH. R11 At 94% RH it holds about 10 wt% water after several hours but about 37 wt% after 5 months. R11 The authors write that at 75% RH and above PEO sorbs significantly more water after 5 months than after hours; in the plot, however, the 5-month points at about 76 and 84% RH lie only slightly above the several-hours points, and the large gap is at 94% RH. C12·X20 Over the 28 days of the spectroscopy experiments, pure PEO compacts and the compacts with ketoprofen, naproxen, ibuprofen, felodipine and ketoconazole took up roughly 0.16–0.215 g of water per g of dry compact (the text: "roughly about 20 wt.%", about 22 wt% when normalized to the PEO content), whereas acetaminophen compacts took up about 0.46 g/g (about 45 wt%, about 50 wt% per PEO). R13·E6 The authors do not discuss why the acetaminophen compacts took up twice as much water. X10

Main result 3: which drug property ranks the outcome. Table C sets the outcome next to the numbers the authors computed.

Table C. Melting data (Table 1), mole-fraction solubilities and activity coefficients (Table 2; values in parentheses as printed, their type not stated), the PEG 400-based estimate (Table 3) and the authors' qualitative grade (Table 3, footnote b). Aqueous solubilities are cited from refs 57–59; the felodipine value has no reference. M1·M2·M3·M4·M5·M6·R14·R16·X16

Three readings follow from Table C. First, the melting data do not rank the outcome: ibuprofen has by far the lowest melting point (74.61 °C) yet only partial loss, and the entropy of fusion of ketoprofen (0.23 J/K/g) is as low as that of felodipine (0.21) and ketoconazole (0.25), which barely changed; the authors state that enthalpy of fusion, entropy of fusion and melting temperature give no correlation. M1·M2·M3·M4·M5·M6·C34 Second, solubility in PEG 400 does not rank it either. All six drugs dissolve well in PEG 400 (mole fractions 0.16–0.32), except ketoconazole, which is an order of magnitude lower (0.02); all activity coefficients in PEG 400 lie below 1, which the authors read as exothermic mixing if the mixing entropy is ideal. R14·C13·C14 The estimate built on these solubilities says that the dry amorphous PEO could dissolve 13–24% of each drug, and 2% of ketoconazole; but felodipine (15%) barely changed while acetaminophen (14%) changed completely, so the authors find "no clear correlation", and for the drugs that did transform the observed loss "appears to be in excess" of the estimate. R16·C21·C22·C23 Third, the activity coefficient in water does rank the outcome. It is of order 10¹ for acetaminophen, 10³–10⁴ for ketoprofen, naproxen and ibuprofen, and 10⁵ for felodipine and ketoconazole, in the same grouping as complete, moderate and negligible loss. R14·R16·C35 In the discussion the authors call this "a clear trend of increased transformation with increased aqueous solubility"; in the abstract and conclusions they say the trends "qualitatively correlate". C35

Two checks on Table C by the AI writer: the activity coefficients equal S^ideal/S within rounding for acetaminophen, ketoprofen and ibuprofen, but for naproxen the printed S^ideal of 0.01 would give γ^{PEG 400} of 0.045 and γ^water of 8.3 × 10³ instead of the printed 0.02 and 3.8 × 10³ (both fit S^ideal ≈ 0.0045), and the two felodipine coefficients imply different ideal solubilities (about 0.022 and 0.031). X5 Neither discrepancy changes the order of magnitude that carries the ranking. X5·R14

Discussion

The authors' mechanism

The discussion assembles the results into a chain. For the crystalline fraction of the drug to fall, three processes "are thought to occur simultaneously": water is taken up into the amorphous regions of PEO, the disordered fraction of PEO grows as a result, and the drug dissolves into the disordered regions (Figure 7). C15 The starting point is the compact itself: crystalline drug touching amorphous PEO at the particle interfaces "can be dissolved by PEO", which the authors label a hypothesis. C16 Dry and at 25 °C nothing happens on the time scale of the study, so the obstacle is kinetic; raising the temperature (as in Schachter's ketoprofen–PEO work) or adding water changes the driving force but "may impart upon the amorphous regions of the system enough mobility" for the thermodynamic end state to be reached. C17·R8·R19

Water has two opposing effects. Because every drug is far less soluble in water than in PEG 400, and water most likely sits in the amorphous PEO that dissolves the drug, the thermodynamic driving force for dissolving the drug into these regions "must be reduced" by water compared with dry amorphous PEO. C24·R14 Yet water speeds the transformation by "two potential mechanisms". C25 First, water (T_g −136 °C) plasticizes the amorphous PEO (T_g about −67 °C), lowering its viscosity and raising the rate at which the system approaches an equilibrium between crystalline drug, a saturated solution of the drug in a water–PEO cosolvent, and crystalline PEO. C26·M7·M12 Second, water lowers the crystallinity of PEO: "It is suggested that PEO may slowly deliquesce", with the slow diffraction changes of Figure 3, the very slow sorption of Figure 5 and the literature deliquescence point of 0.93 water activity as the evidence. C30·R9·R11·R22 The slowness, they add, "most likely" reflects the size of the polymer molecules. C30 Sorbed water makes each unit of the disordered phase a poorer solvent but increases the volume of solvent available, and the enlarged disordered fraction dissolves more drug. C33 The outcome then depends on how well the drug mixes with the wet cosolvent:

In the conclusions the authors put it this way: water "is thought to facilitate the spontaneous transformation by two mechanisms", decreasing the viscosity of the disordered PEO and increasing its amount through deliquescence; the degree of transformation "was related to the ability of the drug to dissolve in the water-amorphous PEO" cosolvent; and "the thermodynamics of the binary systems were useful in describing the dynamic nature of the ternary system". C25·C38·C39 They also note that dissolved drug would "most likely anti-plasticize" the amorphous PEO and that the drug "may alter the thermodynamics of deliquescence". C27·C31

Scope

The evidence covers one polymer (PEO of average M_w about 100,000), one drug loading (10 wt%), physical-mixture compacts, storage at 94% RH for up to 28 days (17 days for the acetaminophen XRPD), and, for the water uptake of PEO, up to 5 months. M7·P1·P2·R11 Only acetaminophen was stored at a second humidity (75% RH), and those data are not shown. R3 The six drugs were all used as crystalline powders and differ widely in aqueous solubility; the grade of crystallinity loss has three levels. A1·R16 The abstract states the general concern that the physical stability of crystalline drugs "may be compromised in the presence of excipients", but only PEO was tested. C41

What it suggests for formulation

The authors draw two practical conclusions: the importance of knowing how many stable and metastable phases a formulation contains and how environmental stresses such as raised RH change them, and the warning that formulating drugs with partially crystalline polymers "may pose interesting problems that may not allow for traditional Arrhenius extrapolations in accelerated stress testing". C39·C40 No stability study at several temperatures was run to test the second point. C40

Note by the AI writer (not discussed in the paper): PEO is widely used as the matrix of extended-release tablets. Within this set of six drugs, the risk of crystallinity loss at high humidity followed the drug's affinity for water, not its solubility in a PEG, which is the proxy a formulator would reach for first, nor its melting point. A water-soluble crystalline drug in a hygroscopic, semicrystalline polymer is therefore the case to test first, and moisture protection matters more for such products than their dry-state phase behaviour suggests. Because acetaminophen changed even at 75% RH, below the deliquescence point of PEO, stress data above about 75% RH should be read with the polymer's own phase change in mind. The doubled water uptake of the acetaminophen compacts also suggests that compact weight gain may be an inexpensive early signal that a drug is dissolving in its matrix.

Limitations

Limitations stated by the authors. The authors are explicit about three. The true solubility of the drugs in amorphous PEO cannot be measured, and whether PEG 400 over- or underestimates it "remains elusive", because end-group and entropy effects pull in opposite directions. C18·C19 The equilibration of PEO with water is very slow, which makes thermodynamic equilibrium states hard to reach experimentally. C29 And the presence of the drug "may alter the thermodynamics of deliquescence", so the literature deliquescence point of pure PEO may not apply exactly to the compacts. C31

The AI writer's own judgement (1): what is measured and what is inferred. The loss of drug crystallinity is shown by two independent techniques and the contrast between drugs in one matrix is large, from an X-ray amorphous halo to persistent drug peaks. R2·R10 But the loss is graded, not quantified: no crystalline fraction was measured, so the statements that the loss "appears to be in excess" of the 13–24% estimates and that there is "a clear trend" with aqueous solubility rest on three qualitative levels across six drugs. X8·C23·C35 For ketoprofen, naproxen and ibuprofen the Raman shifts of 1–2 cm⁻¹ are smaller than the 4 cm⁻¹ spectral resolution, so their grade leans on band broadening and the weaker XRPD peaks; for felodipine the crystalline and PEG 400 reference spectra barely differ in the region shown, so its grade rests mainly on the persistent diffraction peaks. X11·X21 The two controls that make water and PEO both necessary are "data not shown". X7 Most importantly, no measurement locates the disordered drug: the evidence that it "dissolved into the disordered regions of PEO" is the loss of crystallinity plus Raman bands moving toward the PEG 400 solution, which would look the same for an amorphous drug phase or a solution in sorbed water. X17·C37

The AI writer's own judgement (2): deliquescence and the numbers. The deliquescence of PEO is stated more firmly in the abstract ("it was found that PEO undergoes a very slow deliquescence"; "It can be concluded ... the polymer underwent deliquescence") than in the discussion ("It is suggested that PEO may slowly deliquesce"); no PEO solution phase was observed, and the evidence is indirect. X9·C30 Acetaminophen compacts lost crystallinity at 75% RH, well below the cited deliquescence point, so for this drug deliquescence of PEO is not required; the doubled water uptake of acetaminophen compacts could also reflect the drug dissolving in sorbed water, given its far higher aqueous solubility. X10·R3·R13 Several printed numbers need care: the PEO "amorphous fraction of 91%" is the crystalline fraction (Table 3 uses 9% amorphous); the naproxen T_g does not follow from the stated T_g/T_m rule with the Table 1 melting point; some rows of Table 2 are not internally consistent; and the storage temperature, the isotherm method and the method behind the PEO enthalpy of fusion are not stated. X1·X4·X5·X6·X19 The aqueous solubilities are cited from three sources at unstated temperatures, so the activity coefficients in water support a ranking by order of magnitude, not a quantitative relation. X18

Conclusion

The paper makes three contributions. First, it shows by Raman and XRPD that crystalline drugs compacted at 10 wt% with PEO lose crystallinity at 94% RH to very different extents, completely for acetaminophen within about two weeks, partly for ketoprofen, naproxen and ibuprofen within 28 days, and hardly for felodipine and ketoconazole, while dry compacts and the drugs alone are reported unchanged. R2·R4·R5·R6·R7·R8·R10·C36 Second, it shows that PEO itself changes under these conditions: its diffraction peaks weaken and broaden, and its water uptake at 94% RH keeps rising for months, from about 10 to about 37 wt%. R9·R11 Third, it tests which drug property predicts the outcome and finds that neither the melting data nor solubility in PEG 400 does, while the activity coefficient in water does, by order of magnitude. C34·C22·C35 The authors' explanation, that water plasticizes the disordered PEO and enlarges it by a slow deliquescence so that the drug dissolves into a water–PEO cosolvent, fits these observations but was not measured step by step; in their words, water "is thought to" facilitate the transformation, and the trends "qualitatively correlate" with aqueous solubility. C25·C30·C35·C38