How surfactants change the crystal growth of amorphous celecoxib, with and without PVP

Background and motivation

Many new drug candidates dissolve poorly in water. Making the drug amorphous is one way around this: the amorphous form has a higher free energy than the crystal and so typically dissolves faster and reaches a higher, transient solubility (Hancock and Parks, 2000; Hancock and Zografi, 1997). The same excess free energy is also the weakness of the approach, because an amorphous drug can convert back to the crystal and lose its advantage (Otsuka and Kaneniwa, 1988). C1

To keep the drug amorphous during processing and storage, it is usually blended with a miscible polymer to form an amorphous solid dispersion (ASD). The stabilizing effect has been attributed to two things: the polymer raises the glass transition temperature (Tg) of the mixture, an antiplasticizing effect (Khougaz and Clas, 2000; Van den Mooter et al., 2001), and it forms specific interactions with the drug (Andrews et al., 2010; Gupta et al., 2005; Kestur and Taylor, 2010). Earlier work from the same group, which varied the chemistry of the polymer, found that the stronger the hydrogen bonding between drug and polymer, the more the polymer slowed crystal growth in the supercooled liquid; the authors describe the evidence as "strongly" supporting this correlation (Kestur and Taylor, 2010; Kestur et al., 2011). C2·C3

Real formulations are rarely binary. They contain further excipients for dissolution, flow and other properties, and surfactants are among the most common (Aljaberi et al., 2013; Ghosh and Michniak-Kohn, 2012; Rojas et al., 2012; Szuts et al., 2011). Surfactants serve as plasticizers that make melt extrusion easier (Ghebremeskel et al., 2006), help release the drug from the polymer matrix (Qi et al., 2013), and with polymers can give very stable aqueous dispersions of amorphous colloidal particles (Chari et al., 1999); sucrose esters have been reviewed as useful surfactants for drug delivery (Szuts and Szabo-Revesz, 2012). C4

The gap this paper addresses is simple: although surfactants are used more and more in amorphous dispersions, there were "few, if any" studies of what a surfactant does to the crystallization kinetics of the dispersion; the abstract calls the effect "largely unexplored", and the Discussion adds that, "to the best of our knowledge", effects of surfactants on crystal growth rates had not been reported. C5 The authors therefore measured how three surfactants, sodium lauryl sulfate (SLS), D-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) and sucrose palmitate, change the rate at which celecoxib crystals grow from an amorphous matrix, both alone and together with poly(vinylpyrrolidone) (PVP). The stated aim is to learn whether particular polymer–surfactant combinations give dispersions that resist crystallization. A1·A2·A3

Celecoxib, a poorly water-soluble non-steroidal anti-inflammatory drug, is a useful model. It grows crystals quickly compared with indomethacin and felodipine, two drugs studied earlier (Andronis and Zografi, 2000; Kestur and Taylor, 2010), yet the authors found it "quite hard to nucleate" and easy to make amorphous by cooling the melt; under the classification of Baird et al. (2010) it is a slow crystallizer. R15·R16·R17 For a growth-rate study this combination is convenient: the amorphous film stays amorphous until a seed crystal is placed on it, and the growth of that seed can then be followed.

Background concepts

Crystal growth from a supercooled liquid. Above its Tg, an amorphous drug is a supercooled liquid: its molecules can move, but the crystal is the stable form. How fast a crystal front advances into this liquid depends on two opposing factors (Andronis and Zografi, 2000). Close to the melting point (Tm), molecules are mobile but the thermodynamic driving force for crystallization, the free-energy difference between liquid and crystal, is small; growth is said to be under thermodynamic control. As the temperature falls, the driving force grows but molecular mobility drops steeply, and growth comes under kinetic control. A third factor is how many molecules in the liquid have the right orientation to join the lattice. Growth can also differ between the bulk and the free surface, and new growth modes sometimes appear close to Tg (Ishida et al., 2007; Zhu et al., 2008). C25

Tg as a measure of mobility. At a fixed temperature, a mixture with a lower Tg is further above its glass transition and its molecules are more mobile. An additive that lowers Tg is a plasticizer; one that raises it is an antiplasticizer. Small molecules with a very low Tg are strong plasticizers: water, with a Tg of around −133 °C (Angell, 2002), speeds up crystal growth of amorphous felodipine (Rumondor et al., 2010) and indomethacin (Andronis et al., 1997). The authors use this as the template for how a low-Tg surfactant might act. R18·C29

Comparing at equal distance from Tg. If an additive changes the growth rate only by changing Tg, then plotting the growth rate against the temperature above Tg (T − Tg), instead of against temperature, should bring the curves of different mixtures together. The paper uses this replot (its Figure 7) as its main test of the mobility explanation. P7·R12

Melting point depression and driving force. When a miscible additive is present, the drug crystals melt at a lower temperature. A lower Tm means that the liquid has a lower chemical potential relative to the crystal, so the free-energy difference ΔG that drives crystallization at a given temperature is smaller. The authors invoke this effect to explain why one combination grows slowly at high temperatures, where growth is "more dominated by thermodynamic factors". C19·C33

Miscibility. An additive can only change the mobility of the drug if it mixes with it. The paper judges miscibility from three signs: a single Tg that shifts with the additive, a depressed melting point, and changes in the infrared spectrum (shifts of the celecoxib N–H stretching bands or of the PVP carbonyl band) that indicate molecular contact and hydrogen bonding. C24·R5·R6·R7

Polymorphs. Two crystal forms of celecoxib appear in this paper: form III, the starting material, and form I. If a surfactant made a different polymorph grow, the growth rate could change for that reason alone. The paper checks this with X-ray diffraction of the crystals grown from the melt. M1·C37·R14

Seeded radial growth rate. All growth rates in the paper are radial growth rates: a seed crystal is placed at the edge of an amorphous film sandwiched between two cover slips, and the speed at which its front advances (µm/s) is measured from time-lapse images. Because the film is covered on both sides, there is no free surface and the rate refers to bulk growth. P3·C26

Methods in detail

The study has one simple design: one drug, three surfactants and one polymer, each at 10% by weight, tested alone and as surfactant–polymer pairs, with the growth rate of seeded crystals as the main read-out and DSC, infrared spectroscopy and X-ray diffraction used to explain the differences. A second, smaller series varied the PVP level with and without TPGS. A1·A2·A3·A4

Materials and mixtures

Celecoxib came from Attix Pharmaceuticals, PVP K-12 from BASF, SLS and TPGS from Sigma–Aldrich and sucrose palmitate from Carbosynth; their structures are drawn in Figure 1. M1·M2·M3·M4·M5 The three surfactants differ in kind: SLS is an ionic alkyl sulfate, TPGS a vitamin E ester of polyethylene glycol and sucrose palmitate a sugar ester. The Discussion gives melting points of 48 °C for sucrose palmitate (Szuts et al., 2007), 37–41 °C for TPGS (Wang et al., 2011) and 80 °C for SLS, the last without a reference. M3·M4·M5 In the Discussion SLS is called SDS (sodium dodecyl sulfate), the same compound. Note by the AI writer (not discussed in the paper): the SLS structure in Figure 1b is drawn with an alkyl chain of about 19 carbons, whereas lauryl is a 12-carbon chain; the drawing, not the material, appears to be wrong. X10

Binary mixtures of 90 wt% celecoxib with 10 wt% surfactant or 10 wt% PVP, and ternary blends of 80 wt% celecoxib, 10 wt% surfactant and 10 wt% PVP, were prepared in a cryogenic freezer mill; milling conditions are not given. P1 The second series, celecoxib with 3, 5 or 7% (w/w) PVP, each with and without 10% TPGS, appears only in the Results; how it was made, and therefore the exact celecoxib fraction, is not described. P2·X6

Measuring the growth rate

For each run, 2–4 mg of mixture was placed between two 18 mm × 18 mm cover slips, heated above the melting temperature of celecoxib (the methods give 170 °C in parentheses, while Table 1 gives a Tm of 163.46 °C for the pure drug) and quenched to room temperature, which gave an amorphous film. The film was seeded at its edge with celecoxib crystals and placed on a Linkam hot stage under a cross-polarized light microscope, and the advance of the crystal front was recorded by time-lapse images. The growth rate is the slope of front position against time, measured in triplicate at each temperature. P3·R5.a·X12 The methods state a temperature range of 80–120 °C, but the abstract says 70–120 °C and Figures 2 and 3 include points at 70 °C; Figure 4 covers 80–120 °C. X1 Because both faces of the film are covered, the measurements describe growth in the bulk, and the authors assume that the whole temperature range lies where growth "is expected to be mainly controlled by the molecular mobility of the drug molecules". C26

Thermal, spectroscopic and X-ray characterization

DSC. Samples of 3–5 mg in pin-holed aluminum pans were heated at 10 °C/min under nitrogen to find the melting point of celecoxib in each mixture, cooled at 15 °C/min to around room temperature, and reheated at 10 °C/min to find the Tg of the resulting dispersion. The number of replicates is not stated. P4·X7

FTIR. To make interactions easy to see, the celecoxib–surfactant samples for infrared spectroscopy contained 50% surfactant. The TPGS and sucrose palmitate mixtures were dissolved in ethanol and dichloromethane, checked to form a single-phase solution, and spin-coated at 1000 rpm in a nitrogen-purged glove box; the SLS mixture was measured by attenuated total reflectance, because SLS dissolves poorly in organic solvents. Spectra were collected with 128 scans over 4000–400 cm⁻¹. The composition and preparation of the celecoxib–PVP and celecoxib–TPGS–PVP samples are not given. P5·X8

X-ray diffraction. Crystals grown from the melt between cover slips, from celecoxib alone and with 10% of each surfactant, were examined by X-ray diffraction (Figure 9). The instrument, settings and crystallization temperature are not stated, and no PVP-containing sample was measured. P6·X9

The Tg-normalized analysis

Figure 7 replots every growth-rate curve of Figures 2 and 3 against T − Tg, using the Tg of each system from Table 1. Note by the AI writer: the points in Figure 7 sit exactly where the rates of Figures 2 and 3 fall when shifted by the Table 1 Tg values, so the replot is internally consistent. P7·R12

Experimental analysis

Surfactants alone speed up growth; PVP slows it

Figure 2 is the core result. Pure celecoxib grows at about 0.002 µm/s at 70 °C and about 12 µm/s at 120 °C, an "exponential type" increase with temperature of the kind seen for many compounds. R1.a·C6 Adding 10% PVP lowered the rate at every temperature, to about 0.0001 µm/s at 70 °C and 0.42 µm/s at 120 °C; read from the plot, this is a 19–38-fold reduction, which the authors summarize as "more than one order of magnitude". R1.b·C8 Each surfactant raised the rate (Table A). R1·C9

Table A. Radial growth rate (µm/s) of celecoxib alone and with 10% additive, read from the log-scale Figure 2 (approximate; no error bars are plotted). R1

TPGS had by far the largest effect: at 70 °C the rate was about 85 times that of the pure drug, which the text gives as "approximately two orders of magnitude". Sucrose palmitate raised the rate about 7-fold at 70 °C, SLS about 1.5-fold. R1·C9 The effect of all three shrinks as the temperature rises; at 120 °C TPGS is only about 1.4 times faster than the pure drug, SLS about equal and sucrose palmitate slower (about 7.4 against 12 µm/s). R1 The authors note that for TPGS and sucrose palmitate the acceleration was "more marked as the temperature decreased", and in the Discussion they generalise: with surfactants the growth-rate curve is much flatter than for the pure drug, so the dispersions grow at about the pure-drug rate near 120 °C and faster at lower temperatures; "it appears therefore" that the accelerating effect grows on cooling. C10·C36 They contrast this with polymers, whose curves usually run parallel to that of the pure drug, offset to slower rates. C35

The authors rank the surfactants TPGS > sucrose palmitate > SLS, with SLS having "a relatively minor impact". C9 Note by the AI writer: on the plotted points this order holds at 70 and 80 °C only. At 90 °C SLS and sucrose palmitate are about equal (about 0.40 and 0.35 µm/s), and at 100–120 °C SLS is the faster of the two; between 70 and 110 °C SLS runs 1.5–3.3 times above the pure drug, so "very little impact" (Discussion) understates it. X2·C31

Tg, melting point and miscibility

Table 1 gives the Tg and the celecoxib melting point of all eight systems (Table B). PVP raised Tg from 55.34 to 62.40 °C, TPGS and sucrose palmitate lowered it by more than 10 °C, to 44.81 and 44.46 °C, and SLS left it at 55.53 °C, which the authors read as no effect ("did not appear to have any effect"). R5·C16

Table B. Glass transition and celecoxib melting temperature by DSC (from Table 1; each additive at 10%). The last column is computed by the AI writer from the printed values. R5

In the ternaries, PVP did not raise the Tg of the TPGS system (44.17 against 44.81 °C), the SLS–PVP system fell to 51.17 °C, below both its binaries ("slightly unexpected"), and only the sucrose palmitate–PVP system (51.47 °C) lay between the surfactant–drug and polymer–drug values, as expected. R5·C17 All additives lowered the celecoxib melting point. The authors describe the single-additive depression as "around 3–4 °C" and the effect of two excipients as additive, with the largest drop, 12 °C to 151 °C, for TPGS plus PVP and about 156 °C for the other two ternaries. C18 Note by the AI writer: Table 1 gives single-additive depressions of 1.68 to 4.49 °C, not 3–4 °C, and the SLS depression (1.68 °C) is of the same order as those of TPGS and sucrose palmitate, although the Discussion cites an "invariance" of the SLS melting point as evidence of immiscibility. No replicate values are given, so Tg differences below about 1 °C, such as 55.53 against 55.34 °C, cannot be judged. X3·X7

Infrared spectra add the molecular picture. In crystalline celecoxib the two N–H stretching bands lie at 3335 and 3223 cm⁻¹; in the amorphous drug they move up to 3364 and 3269 cm⁻¹, which the authors read as weaker hydrogen bonding between celecoxib molecules in the glass than in the crystal (Figure 5). R6·C20 With PVP the lower band moved down to 3192 cm⁻¹ and the PVP carbonyl band from 1681 to 1668 cm⁻¹ (the latter "data not shown"), indicating hydrogen bonds between celecoxib and PVP. R7·C21 With TPGS the N–H region changed considerably (Figure 6): the two bands of the amorphous drug merge into one broad band peaking near 3230 cm⁻¹ (read from the figure), and in the ternary with PVP the carbonyl band shifted slightly further, to 1661 cm⁻¹. R9·R10·C23 Sucrose palmitate caused no N–H shift, read as "no major H-bond interactions", and the SLS blend spectrum was simply the sum of the two pure spectra. R8·R11·C22

From these data the authors conclude that sucrose palmitate and TPGS are miscible with celecoxib "to some extent", while SLS is "largely immiscible" and separates as a crystalline material at room temperature; the micrograph of the SLS sample at 120 °C shows an amorphous region speckled with fine particles (Figure 8c). C24·R13 They link the plasticizing effect of the two miscible surfactants to their low melting points (48 °C and 37–41 °C), which "are expected to" mean low Tgs. C28 Note by the AI writer: the FTIR samples contained 50% surfactant and were spin-coated from solvent, whereas the growth samples contained 10% and were melt-quenched, so the spectra show what the components can do rather than what happens in the growth films. X8

Does Tg explain the surfactant effect?

If the surfactants act only by lowering Tg, the curves should coincide when the growth rate is plotted against T − Tg. The authors find that, after this correction, the growth rates of the surfactant systems "are fairly close to each other", "indicating that the main effect of these additives is most likely in influencing the mobility of the celecoxib molecules". C30 Table C compares the binary systems at about the same distance above Tg with the same systems at the same temperature.

Table C. Growth rate (µm/s) of the binary surfactant systems at the same temperature and at about the same T − Tg, read from Figures 2 and 7 (approximate). The spread row is computed by the AI writer. R1·R12

Note by the AI writer: the correction does narrow the differences, from about 85-fold to about 12-fold at the low-temperature end, so Tg accounts for much of the surfactant effect. It does not remove them: at about 25 °C above Tg, TPGS still grows about 8 times faster than celecoxib, and sucrose palmitate stays 1.2–3.8 times slower than celecoxib over the whole range. The correction also leaves the ternary systems far apart: at about 26–29 °C above Tg, TPGS plus PVP grows at about 0.00006 µm/s, PVP alone at about 0.0063, sucrose palmitate plus PVP at about 0.0019 and SLS plus PVP at about 0.012. The paper does not discuss the ternary points of Figure 7. X4·R12 Molecular mobility itself was not measured. C30

Surfactants together with PVP

Figure 3 shows what happens when 10% surfactant and 10% PVP are present together (Table D). With SLS or sucrose palmitate, growth was faster than with PVP alone, for sucrose palmitate only "at lower temperatures"; the authors call this "perhaps not surprising", since "it might be expected" that the ternary rate averages the separate effects of surfactant and polymer. R2·C11·C12 Read from the plot, SLS plus PVP grows about 2–20 times faster than PVP alone across the range, while sucrose palmitate plus PVP is faster at 70–90 °C (about 5.6-fold at 70 °C) and slower at 100–120 °C (about 0.15 of PVP alone at 120 °C). R1.b·R2.a·R2.c

Table D. Radial growth rate (µm/s) with 10% PVP, alone and with 10% surfactant, read from the log-scale Figure 3 (approximate). The PVP-only points are the same as in Figure 2. R1.b·R2

The combination of TPGS and PVP was the surprise. It grew more slowly than PVP alone at every temperature, making it, in the authors' words, "the most stable of all the systems studied, at least at higher temperatures"; the Figure 3 caption calls it a synergistic effect. R2.b·C13 The size of the advantage depends strongly on temperature: about 35-fold at 120 °C (about 0.012 against 0.42 µm/s) but less than twofold at 70 °C (about 0.00006 against 0.0001 µm/s). R1.b·R2.b·X5 Tg does not explain it, since the Tg of the TPGS ternary (44.17 °C) is no higher than that of celecoxib–TPGS. R5.e·R5.f·C17 The authors instead point to the melting point: TPGS plus PVP depresses Tm most, which lowers the driving force for crystallization and "could contribute to the lower crystal growth rates observed for that system, in particular at higher temperatures where the growth rate is more dominated by thermodynamic factors". C33 The crystals that grew in this system at 120 °C also looked different: a large faceted plate instead of the fibrous, needle-like fronts of the other systems (Figure 8e). R13·C34

For SLS the authors give a different explanation. In the binary, SLS hardly mixes and "as a consequence" has very little effect; with PVP present, both Tg and Tm fall, which they read as PVP increasing the miscibility of SLS ("appears to increase"); the now-mixed SLS, which melts at 80 °C and so should have a low Tg, then speeds growth, so the SLS ternary grows faster than celecoxib–PVP. C31·C32 Note by the AI writer: the melting point alone does not order the ternaries. SLS plus PVP has a larger Tm depression (7.33 °C) than PVP alone (4.49 °C) yet grows faster at every temperature, and sucrose palmitate plus PVP (8.09 °C) grows slower than PVP alone only from 100 °C up; the authors' "could contribute" is the right strength for this argument. X13

The temperature crossover at lower PVP levels

Because the TPGS–PVP effect was so marked, the authors measured lower PVP levels, 3, 5 and 7%, each with and without 10% TPGS (Figure 4, Table E). With TPGS the growth-rate curve has a lower slope against temperature, so each pair of curves crosses; as PVP rises from 3 to 5 to 7%, the crossing moves from 110 to 100 to 90 °C. R3·R4·C14

Table E. Radial growth rate (µm/s) at the ends of the measured range, read from Figure 4 (approximate; error bars shown in the figure, type not stated), with the crossing temperatures stated in the text. On the plot the 3% crossing lies just above 110 °C. R3·R4

Above the crossing, TPGS slows growth; below it, TPGS speeds it up. The authors conclude that "the synergistic effect of combining the polymer and surfactant only persists over a limited temperature range", and that below a temperature that depends on polymer concentration "the system with just polymer has the slower growth rate". C15 With 10% PVP no crossing occurred down to 70 °C (Figure 3), in line with the crossing temperature falling as PVP rises. R2.b·R4 The Tg and Tm of the 3–7% mixtures were not reported, so the crossover cannot be related to them. X6

Polymorph and crystal morphology

The authors considered "one possible explanation" for the surfactant effects: that a different polymorph grew. X-ray diffraction of crystals grown from the melt (Figure 9) showed that with TPGS and sucrose palmitate the growing form was the starting form III; with SLS, "some amount of form I was clearly detected", with a distinguishing peak at 8° 2θ. C37·C38·R14 So the large TPGS and sucrose palmitate effects are not due to a polymorph change. Note by the AI writer: no PVP-containing sample was examined, including the TPGS–PVP system whose crystal at 120 °C looked unlike all others, and the SLS rates may mix the growth of two forms. X9

Discussion

How the authors connect the results

The authors' reading rests on one assumption and one question. The assumption is that, over the range measured, celecoxib growth is controlled mainly by molecular mobility, with the thermodynamic driving force mattering only near the melting point ("is expected to be"). C25·C26 The question, for each additive, is whether it mixes with the drug, because only a miscible additive can change Tg and so mobility. C24·C40 The chain they draw is summarized below.

Within this chain, the binary results fit well: the two surfactants that mix and lower Tg speed growth the most, and the one that does not mix (SLS) changes Tg not at all and growth comparatively little. R1·R5·C24 The growth-rate curves of the surfactant systems are flatter than that of the pure drug, so the surfactant effect grows as temperature falls, which is what a mobility effect would do in a regime where mobility dominates. C36·C10 The ternary results fit less neatly, and the authors say so: the combined effects were "highly complex", and it is "currently difficult to predict how growth rates will be affected in the presence of both a polymer and a surfactant". C43·C41

The TPGS–PVP combination

The most interesting result is the one the authors did not expect: TPGS, the strongest accelerator on its own, together with PVP gave the slowest growth of any system. C13 Its Tg is no higher than that of celecoxib–TPGS, so a mobility argument cannot explain it. The authors' explanation is thermodynamic: the combination depresses the celecoxib melting point by 12 °C, which lowers the driving force for crystallization, and this "could contribute", especially at high temperature. C17·C33 The crossover experiment supports the idea that something besides mobility is at work, since the TPGS-containing curves have a different slope from the PVP-only curves and cross them at temperatures that fall as PVP rises. R3·R4·C14 The infrared data add a further, untested possibility: in the ternary the PVP carbonyl band shifts slightly further (1661 against 1668 cm⁻¹), so TPGS may change how PVP and celecoxib interact. R10·C23 Note by the AI writer (not discussed in the paper): the crystal that grew in this system at 120 °C was a large faceted plate unlike all others, and its polymorph was not checked, so a change of crystal habit or form is a third candidate that the paper cannot exclude. R13·X9

What it means for formulation

The authors' practical message is direct. Surfactants added for processing or release can reduce the physical stability of an amorphous dispersion, and "in general", a surfactant that is miscible with the drug and plasticizes it "would be expected" to increase the growth rate. C40 A polymer "in general" offsets this acceleration, but how much cannot yet be predicted, so it is "clearly important to consider the impact of each formulation component, alone and in combination, on the physical stability of the dispersion". C43·C44 They call for studies over a wider temperature range and with other drugs and polymers. C39

Note by the AI writer (not discussed in the paper): two features of the data matter for practice. First, the surfactant penalty grows on cooling: for TPGS from about 1.4-fold at 120 °C to about 85-fold at 70 °C. Storage temperatures lie below the measured range, so a surfactant that seems harmless in a high-temperature screen may matter most in storage. R1 Second, the benefit of PVP plus TPGS also changes with temperature: it is about 35-fold at 120 °C, less than twofold at 70 °C, and at 3–7% PVP it reverses below 90–110 °C. A good result at extrusion-like temperatures should therefore not be carried over to storage without measuring there. R2.b·R4·X5 A Tg drop of about 10 °C from only 10% surfactant is a simple warning sign that can be measured early. R5

Limitations

Limitations stated by the authors. The authors describe the ternary systems as "highly complex" and say it is "currently difficult to predict" growth rates when a polymer and a surfactant are both present; "additional studies in this area are warranted". C43·C41 They frame the opposing effects of surfactants and polymers as something to be explored "over a greater range of temperatures" and with "other compounds and polymers". C39 Their conclusion that the surfactant effect is on mobility is hedged as "most likely", and the melting-point explanation for TPGS plus PVP as "could contribute". C30·C33

The AI writer's own judgement.

• The growth-rate effects themselves are large and directly measured in triplicate, and Figure 7 is internally consistent with Figures 2 and 3. The main conclusions about direction (surfactants faster, PVP slower, TPGS plus PVP slowest) are well supported. R1·R2·R12
• Several stated rankings and magnitudes do not match all plotted points: the surfactant ranking holds only at 70–80 °C, SLS is not without effect, and the single-additive melting-point depression is 1.68–4.49 °C rather than 3–4 °C. X2·X3
• Molecular mobility, the proposed mechanism, was not measured; the Tg correction narrows but does not remove the binary differences and leaves the ternaries far apart. The driving-force argument was not quantified and does not order the ternaries. X4·X13
• The infrared evidence for miscibility comes from 50% surfactant films prepared by spin coating, not from the 10% melt-quenched growth samples; the PVP sample compositions are not given. X8
• Table 1 has no replicates or spreads, yet differences of a few tenths of a degree are interpreted. Figures 2, 3 and 7 show no error bars although the growth rates were measured in triplicate. X7·R1·R2
• The polymorph was not checked in any PVP-containing system, including the TPGS–PVP crystal of distinct habit; the SLS samples partly grew form I. X9
• The temperature range is stated as 80–120 °C in the methods but 70–120 °C in the abstract and figures; the 3–7% PVP mixtures are not described; the SLS structure in Figure 1b is drawn with the wrong chain length. X1·X6·X10
• All data come from one drug, one surfactant level (10%), one PVP grade and temperatures 15–76 °C above the Tg of the systems; nothing was measured near storage temperature. P1·A4·R12

Conclusion

This short paper measured what surfactants do to the crystal growth of an amorphous drug, an effect that, to the authors' knowledge, had not been reported before. C5 In seeded, melt-quenched films of celecoxib, 10% of SLS, TPGS or sucrose palmitate raised the growth rate, TPGS by about two orders of magnitude at 70 °C, while 10% PVP lowered it more than tenfold. R1·C8·C9 The two surfactants that mix with celecoxib lower its Tg by about 10 °C, and the authors attribute their effect "most likely" to higher molecular mobility; the Tg-normalized replot supports this in part. R5·R12·C30 With PVP present, SLS and sucrose palmitate still raised growth at lower temperatures, but TPGS plus PVP grew slowest of all, an advantage that shrank on cooling and, at 3–7% PVP, reversed below 90–110 °C. R2·R4·C13·C15 The authors' conclusion is that the combined effects of polymers and surfactants are complex and must be tested component by component and in combination. C43·C44