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X. EVAPORATION vs COOLING

Since crystallization can proceed either through solvent evaporation or temperature control (cooling), the question is:
Which one is more conducive to the crystallization of DMT?

Figure 26. Solubility curve for DMT, with dashed lines showing comparison of solubilities at different temperatures

DMT Solubility, Pull 2

mg/mL
Temp (oC)
solvent
21.0 4.69
36.5 6.61
45.8 13.73
57.0 18.14
68.0 23.53
76.4 26.94
84.7 29.25
95.0 38.93

As seen in the figure above, DMT exhibits very low solubility in n-heptane at temperatures below 40oC, while the
solubility at temperatures exceeding the melting point steadily increases.
Most of us have probably observed that the majority of crystals form relatively early on in the crystallizing process, and
leaving it out for the solvent to fully evaporate doesn’t yield much more. Looking at the solubility curve, it’s easy to see
why this is, as the following figure illustrates:

mg
Solubility at RT : 4.69 /mL Starting amount : 1.947 g
o mg
Solubility at 95 C : 38.93 /mL Volume solvent : 50 mL

Amount of crystals to be deposited : 1712 mg

Amount of crystals remaining : 235 mg

As shown, 1.71g will be precipitated out during the transition from 95oC to 21oC if you begin with 1.95g and use 50mL of
solvent. After this occurs, only 0.235g will be available for subsequent crystallization, which accounts for the lack of
additional crystals seen after the initial burst.

Problems with evaporative crystallization:

1. “Penetration beyond the supersolubility curve into the labile zone rarely happens, as the surface from which
evaporation takes place is usually supersaturated to a greater degree than the bulk of the solution. Crystals
which appear on this surface eventually fall into the solution and seed it, often before [the solution
concentration hits the metastable zone limit] in the bulk of the solution” 1
a. What this means is that while evaporation should raise the solution concentration (‘upwards’ arrow on
solubility curve), the concentration in actuality can’t rise to supersaturation levels, since anything
generated by the supersaturation as solvent is evaporating would be deposited as crystals and thereby
lowering the solution concentration back down again
2. “In evaporative crystallization, crystals are sometimes observed to form preferentially near the surface of the
solution, due to a higher local concentration of solute” 2. (This applies to cooling surfaces too, i.e. vessel walls)
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XI. NATURAL vs. CONTROLLED COOLING

Sections VIII & IX introduced the idea of controlled crystallization by fine-tuning the amount of cooling as well as cooling
rate. DMT is most suitable for crystallization by temperature control by virtue of its low RT solubility and the fact that its
solubility increases dramatically with increasing temperatures, creating a large driving force for crystallization to occur.

Simulation of the effects of heating and cooling on a DMT crystallization process

In order to study and attempt to quantify the natural process of cooling a DMT solution at RT after taking it off the hot
plate, I decided to mimic the process by crystallizing different APIs in an organic solvent similar to heptane. To this end I
employed the use of ibuprofen and later acetaminophen standards to replace the DMT, and acetonitrile to replace the
n-heptane. Both worked well, but acetaminophen seemed to match DMT the closest on account of its similar solubility
in acetonitrile as DMT has with heptane. Recrystallized acetaminophen also appears quite similar to crystalline DMT.

Unfortunately I didn’t have my thermocouple with me for these experiments, but fortunately enough temperature and
evaporation rate are tightly coupled, and in the following examples the evaporation rate can easily enough be
conceptually replaced with temperature.

Study 1: Ibuprofen
1.99g of ibuprofen standard was added to 68.1 mL of warm acetonitrile and heated for 11 minutes on a hot plate set to
90oC (technically 10 min at 90C, and 1.5 min at 80C). The hot plate was then turned off and evaporation measured
during the first cooling cycle. At 35 min the hot plate was turned back on, to 65oC this time, and at 50 min the
crystallizing solution was taken off the plate and left to sit at RT until further measuring the next day.

Figure 27 shows the evaporation rate as a function of the temperature cycling within the first 2 hr, and Figure 28 depicts
the overall curve for a solution cooled naturally. Notice how sharply the decrease is as soon as the solution is taken off
the hot plate. Keeping in mind the extreme sensitivity to temperature exhibited by the solubility behavior of DMT,
cooling a solution in this way will result in spontaneous and uncontrolled nucleation, producing many small crystals.

Figure 27. Heating and cooling rates for the first 120 min of Study 1
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The overall curve seen in Figure 28 is a prototypical example of a natural cooling profile, and it’s what we want to avoid
at all costs when we engage in the crystallization of DMT because it represents the antithesis of crystal control.

Figure 28. Final measurements for a naturally cooled crystallizing solution, Study 1

Figures 29 & 30 compare this type of cooling with two other methods, constant (or linear) cooling and controlled (or
parabolic) cooling, while Figure 31 correlates the effects on supersaturation evinced by the different cooling methods.

Figures 29 & 30. Comparison of natural, constant, and ideal cooling profiles 9

Figure 31. Effects of natural cooling and controlled cooling on supersaturation over time 1
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From Figure 31 it is evident that natural cooling will produce a supersaturation peak early on in the process. If such an
event occurs, rapid and uncontrolled, heavy nucleation will be inevitable. This applies especially to DMT, where even
relatively small increments of temperature decrease will vary the saturation concentration considerably. In order to
make the nucleation process controllable, one should choose a cooling path similar to the idealized ones above which
will allow for a constant low level of supersaturation to be maintained.

Figure 32 does a good job at highlighting the interplay of different cooling profiles with supersaturation, nucleation rate
and growth rate. It also offers a solid explanation of experimental observations with typical DMT crystallization
processes, such as an early boom in crystal nucleation and growth followed by a period of relative quiescence. On the
flip side, it shows us what we might expect our DMT crystals to look like if we were to follow a cooling path that
provided constant supersaturation levels like in 7(c). In such a case we’d expect our crystals to be large and few.

Figure 32. Linear and non-linear cooling profiles and corresponding effects on growth rate and nucleation rate 13
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An approach to generating a cooling profile that closely approximates what is considered ideal is shown in Figure 33
below, which recommends a three-step system of linear ramps.

Figure 33. Approximating a non-linear cooling curve by a three-step linear approach 13

Study 2: Acetaminophen (I)

In this round I sought to mimic the DMT process a little better by heating the API solution separately and then
transferring it to another dish, also preheated. The heating was stepped down gradually, from 85oC to 50 oC over the
course of ~2.5 hr followed by a hold at 45 oC for another 2 hr or so. The results are shown with the 3rd study in Figure 34,
and show that the cooldown process was still way too fast, and not all that different from the 1st study even.

Study 3: Acetaminophen (II)

In this instance, the solution was prepared at RT and then heated on a hot plate set to 80 oC and reduced to 60 oC over
the course of 90 min before being taken off. In Figure 34 it can be seen that this would appear to be a more effective
way of maintaining the temperature after a solution is let to cool at RT, but when we look at Figure 35 it is clear that the
overall cooling profiles of all three solutions represent the so-called ‘natural’ cooling behavior and thus is less than ideal.

Figure 34. Cooling profiles of all 3 solutions, from t= 0 to t= 300 min

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Figure 35. Complete cooling profiles for all 3 solutions

XII. EVAPORATION RATES AND CONCENTRATION CHANGES

The principle motivating factor for the above studies was to measure evaporation rates in an attempt to quantify
concentration changes as a function of temperature when a crystallizing solution cools. It is imperative in the
crystallization of DMT to know exactly what the working concentration of solution is at any given moment and for any
given temperature. Only then is it possible to control the crystallization process by maintaining the supersaturation
closely within the metastable zone.

Some basic relevant questions we might ask during a crystallization process are:
1. “How much will my solution’s concentration change while I’m keeping it on the hot plate?”
2. “How much total solvent am I losing during the heating process (or cooling)?”
3. “What is the evaporation rate when my hot plate is set to (X)oC ?”
4. “What is the actual temperature of the solution if I set my hot plate to (X)oC ?”

Solutions to these questions are found in the graphs below. Knowing that math isn’t everyone’s thing, though, I tried to
make things simple by compiling all of the calculations for the questions above in the supplemental Excel sheet. So if it’s
not for you don’t even worry about it, just fill out a few squares in the Excel sheet and you’re gold.

Figure 36. Concentration changes and total solvent loss during the heating process
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The concentration of a solution will change as a function of the heating temperature according to the following
relationship, where y = concentration (mg/mL solvent) at time t (min):
y = (starting concentration) * e(kt)
where k = a constant dependent on the working temperature with a range of k = 0.0051 to k = 0.0035, with
lower temperatures yielding a lower value for k.

The amount of solvent lost during this period was fairly consistent between all three trials and followed a more or less
linear pattern, with the average coming out to:
y = 0.2718(t)

where y in this case is measured in mL of solvent

Figure 37. Evaporation rate as a function of hot plate temperature setting

This is what I wanted probably the most -- to be able to predict the evaporation rate at any temperature. A solid
relationship can be found in the equation:
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y = 0.0083*(T)1.779

where y = evaporation rate (mL/hr), T = Temperature (oC), and the rest are constants

Finally, there is the matter of correlating the temperature reading your hot plate outputs with the actual temperature of
the solution, in order to account for heat loss through the crystallizing dish or through dissipation. Here is when I used a
thermocouple in a closed system (no evaporation) and found the following results seen in the figure below:

Figure 38. Relation between temperatures, theoretical vs actual

In Figure 38, the temperature at which the hot plate was set is drawn with black lines, and the solution temperature is
given in blue. The overall trend was quite linear, with the relationship being equivalent to:

y = (0.890)x – 10.183

where y is the actual temperature and x is the temperature as read by the hot plate.

XIII. FINAL RESULTS FOR SOLUBILITY OF DMT IN HEPTANE (FULL)

A. PULL 1:
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B. PULL 2:
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C. PULL 3:
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Difference between graphing methods: mg/mL vs mmol/mol
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POLYMORPHS: THE TRIMORPHIC SYSTEM OF DMT

3 polymorphs at least are visible,

2 of which are enantiomers,
1 of which is monotropic

MELTING POINTS OF POLYMORPHS, LITERATURE & EXPERIMENTAL:

Figure . Summary of melting points from various sources correlated with own experimental results
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Van’t Hoff plot for pulls 1 – 3, with additional data for pull 4 + extra sampling. Estimated transition points drawn in
dashed lines

Figure . Correlation between solvent temperature at time of recrystallization and the resultant product’s solubility at
room temperature. (Black trendline = power equation, Red trendline = exponential equation)
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(Attempts to unravel the polymorph mystery)

Figure . Source: P2
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Figure . (P4)
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Solvent-Mediated Phase Transition (SMPT) (P1):

1. In essence, is a competition of growth and dissolution of two polymorphs about the transition temperature (Tt)
a. > Tt , one form grows at the expense of the other
b. < Tt , the opposite is true
2. Pull 1:
a. Pulled at 80oC and collecting into a single crystallizing dish
b. After some time, precipitate formed on the bottom (1B) –
i. Most stable form (lower solubility)
c. Top layer containing the more soluble form was separated and placed into new dish (1A)
i. Metastable form
ii. How did metastable form happen, unless this first pull picked up two polymorphs in the
beginning?
1. Likely that the initial total sample contained polymorphs carried through the salts
d. The metastable form in 1A deposited crystals (small + large) which in a later study measured as the
lowest solubility of all the pulls and hence the most stable
i. SMPT ??
e. The stable form in 1B deposited amorphous mass which had considerably higher solubility than seen in
that in 1A,
i. Since solid phase transformations can only be carried out from a less stable solid phase to a
more stable solid phase,
ii. This increase in solubility exhibited in the 1B dish is likely due to [poly?]amorphous nature
f. Competing kinetics of dissolution and growth
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i. “When the metastable polymorph is completely dissolved [as it was after the mixed solution
was given time to settle and gain supersaturation then equilibrate back], the stable polymorph
continues to grow until its solubility is reached within a certain amount of time that depends
on the position of the supersaturation plateau”
3. The driving force of the SMPT is the difference in solubility between solid forms.
a. SMPT is made easier when the difference in solubility between solid forms is large
i. The more soluble a substance in a solvent is, the faster the transformation from the metastable
form to the stable one
1. Larger exchange rate of molecules between forms due to higher solubilities

Figure . Explanation for Sample 80H EX (Sample taken at 65.0oC) ?? P4

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PRECIPITATION DIAGRAM FOR POLYMORPHIC SYSTEMS

Relation to FAS[A]. Probability of polymorphic DMT salts

5
Figure .
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