DEFINICIÓN DE LA GESTIÓN BASADA EN PROCESOS

are three types of thermograms that may be obtained from DSC scanning of a pure substance which has two polymorphs.

(1) One which shows a solid-solid transition before melting (of a more stable

form), ie. a thermogram with two endothermie peaks; one very small and the other bigger. The heat of transition is usually smaller for solid-solid phase change than solid- liquid phase change (Timms, 1984)

(2) One which shows the melting of a metastable polymorph (an endotherm),

then a recrystallisation from the melt to a more stable form (an exotherm), and the melting of the stable polymorph (another endotherm). Figure 1.5 (solid line) in Chapter

1 illustrates this type of thermogram.

Depending on the scanning speed, either (1) or (2) may be obtained as shown, for example, by Behme et al (1985) in the study of an anxiolytic drug, gepirone and Schlichter et al (1987) and Garti et al (1989) in the study of tristearin. Slow scanning speeds (1° and 2°C/min in tristearin; 2.5°, 5° and 10°C/min. in gepirone) allowed a solid state transformation while faster ones (5° and 10°C/min. in tristearin; 20° and 40°C/min. in gepirone) only allowed a melt-mediated one.

(3) One in which each polymorph melts without any transition to the other form,

neither solid state nor melt-mediated transition (Giron, 1986).

In the circumstances when a substance has more than two polymorphs the solid-solid transition, melting and crystallisation may overlap leading to difficulties or even misunderstanding in the interpretation of a DSC curve. The overlap of transitional events may also be true for a mixture of substances which exhibit polymorphic nature, such as a mixture of triglycerides.

Polymorphic transformations may occur during scanning. It is therefore difficult, sometimes even impossible, without additional evidence, to judge whether the DSC curve represents the state of a sample before the scanning or is only a result of an induction

of the heating itself. Two examples provided below reflect clearly the nature of this difficulty. In addition, they show how the choice of scanning speeds were selected to suit the phenomenon the investigators wanted to study.

Tuladhar et al (1983) found that the DSC curve of polymorphic form E of phenylbutazone had only one peak (around 370K) when a scanning speed was >32°C/min. This peak represented the melting of the drug. When a scanning speed was less than 32°C/min. (16°, 8°, 4° and 2°C/min.) three peaks were found. These were an endothermie around 370K followed by an exothermic and an endothermie at 375.5°- 378.5°K, depending on the scanning speed. This new thermogram represented the melting of form E and the recrystallisation and melting of a new polymorphic form (Form A), respectively. Liversidge et al (1981), working with tristearin, observed similar results. A fast scanning speed (15°C/min.) resulted only in the melting of a - form of tristearin. Slower scanning speeds (8°, 6°, 4°, 2° and l°C/min.), however, allowed the transformation of a-form into higher polymorphic forms, although the thermograms were more complex than those of phenylbutazone.

Tuladhar et al (1983) went on to use a scanning speed of 32°C/min. to investigate the thermal properties of phenylbutazone crystal forms before and after grinding. They found that Form E appeared to be partially converted to Form A on grinding. It is obvious that slow heating rates, which also induced the change, could not be used to investigate this effect of grinding. On the other hand, since the maximum number of transitions was given by a scanning speed of 2°C/min., Liversidge et al (1981) used this rate to study the storage effect on melting behaviour of triglycerides and commercial suppository bases and to construct the phase diagrams of tristearin and other triglycerides.

1.4 DSC in the Study of Fats / Gelucire Systems

1.4.1 Practical consideration : a scanning speed

The principles described in 1.2 and 1.3 in this chapter can be applied in the DSC studies of gelucires or other fats. Obviously, a scanning speed is a very important factor

Chapter 3 ...D S C Studies /107

that should be considered carefully when working with a solid dispersion and polymorphism. The fact that fats have a very low thermal conductivity (Sonntag , 1979)

probably makes the situation even more difficult. In modern DSC equipment the

platinum thermocouple is placed outside the sample, hence the temperature indicated by the machine is not necessary the same as the sample. Furthermore, a temperature gradient in the sample can exist as a result of poor heat transfer, which makes the use of high scanning speed inadvisable. As demonstrated by Kawamura (1979), a change of a scanning speed from 10°C/min. to 40°C/min. increased a melting point of polymorph form A (a tentative term) of palm oil from 300°K to 315°K. On the other hand, results from a slow scanning speed may not reflect the actual state of a sample.

There is a consensus for the use of low scanning speeds, ie. l°-5°C/min. in the DSC studies of suppository bases (Coben and Lordi, 1980; Yoshino et al, 1981; Wesolowski, 1982; Liversidge et al, 1981, 1982; Laine et al, 1988; Fabregas et al, 1991; De Muynck and Remon, 1992). The reason given by these investigators is that speeds higher than 5°C/min totally wash out and shift the sharp peaks observed at slower scanning speed.

In fats and oils chemistry, the scanning speeds used are more diverse, probably just because many more studies have been done than in pharmaceutical. For example, an unusual high rate of 80°C/min was used by Busfield and Proschogo (1990a, b) in the study of palm stearine (a solid part of palm oil). The reason for this, as described in previous section, is that at high scanning speed there is less chance of any structural reorganisation occurring during the time of the scan, so that the thermal characteristics observed relate more closely to the morphology of the sample existing at the start of the scan. At lower scan speeds, structural reorganisation can occur during the scanning process (Busfield and Proschogo 1990a, b). However, when a very fast speed has been used, it was usually accompanied by slower scanning speeds to complement the interpretation of the results (Kawamura, 1979; Busfield and Proschongo, 1990a, b).

1.4.2 A hypothetical binary mixture of fats

To aid the interpretation and discussion of the results in this study, it may be helpful to discuss the thermal behaviour of a hypothetical fat. Since even the simplest fat such as cocoa butter would require consideration of at least five triglycerides to even approximate its behaviour, it is clearly not possible to depict the true situation. Instead, consider a fat containing two components X and Y as shown in Figure 3.2. X and Y are assumed to have stable B and B' polymorphs respectively. A mixture of X and Y is a eutectic system with partial solid solubility.

At composition a^a^, a simple binary mixture fat, Sx(B) (a solid solution of Y in X), showing a single stable B polymorph exists but melting over a temperature range between the solindex and liquidas lines. At composition bib2, a fat showing a broad melting range occurs but now the fat is a mixture of two solid solutions Sx(B) and Sy(B3(a solid solution of X in Y) with both B and B' polymorphs present together. As the temperature is increased, the Sy(B') disappears when the solidus line is crossed, leaving Sx(B) which disappears when the liquidas line is crossed. In this case, a natural disappearance of polymorph, ie. B' before B, is observed but the two are not related as in the case of a pure triglyceride.

At composition fjf2, a fat which is a mixture of solid solution Sx(B) and S y(B 3 can again be observed except for that Sx(B) will melt before Sy(BO if the temperature is

raised. In other word, B polymoiph melts before B' polymorph. At composition g^g2,

which is a eutectic composition, a solid solution Sx(B) and Sy(B') will melt at the same

temperature, ie. B and B' polymorph have the same melting point. These two situations

are not possible for a single pure triglyceride and are the reasons why the polymorphic behaviour of a real fat is much more complicated. Finally, at composition hih2, the situation is similar to the one at a^a2, but B' polymorph (a solid solution S y (6 ')) is observed.

The above reasoning can be assumed to extend to a mixture of many components in which case more than two solid solutions may co-exist their number and composition

Chapter 3... DSC Studies / 109