Polymorphic transformations drying

Polymorphs are different crystal forms of the same compound [55], They are usually prepared by crystallization of the drug from different solvents under diverse conditions. However, exposure to changes in temperature, pressure, relative humidity, and comminution which are encountered in processes such as drying, granulation, milling, and compression may also lead to polymorphic transformations. 

For polymorphic compounds, such as sulfa drugs, talc excipients induced polymorphic transformation of sulfamethoxazole during the process of microencapsulation by spray-drying,... 

Polymorphic transformation can take place during pharmaceutical processing, such as particle size reduction, wet granulation, drying, and even during the compaction process.f Tests employed to determine crystal... 

Otsuka et al. studied the effect of humidity and drying on the polymorphic transformation rate at 45 C for six forms of phenobarbital [28]. Figure 4 shows that the monohydrate (Form C) and the hemihydrate (Form E) slowly convert to the anhydrous Form B under high-humidity stress conditions (45°C and 75% RH), while the conversion is very fast at low humidity (45°C and 0% RH). This is reasonable, since the driving force to form anhydrous material is a dry environment. The key point of Figure 4 is the rapid conversion of phenobarbitol in less than 12 at 45°C and 0% RH, which represents very reasonable processing conditions for an industrial drying oven. 

But of course, there are drawbacks in using solvents. Because there are not totally inert they may favor the formation of undesirable impxu-ities inthe intermediates of synthesis and in the DS. Regarding the manufacture of the DP, the solvents, including water, may induce either polymorphic transformations or formation of solvates (hydrates) which, after drying, could lead to a desolvated solvate with quite different physical properties impacting potentially either positively or negatively on the DP performance. ... 

Matsuda et al [146] provided evidence, via DTA, of the polymorphic transformation in spray dried phenylbutazone encouraged by varying the inlet temperature from 30° to 120°C. Importantly and indicative of its use, TGA was utilised to confirm that there was no residual solvent in the sample, in the form of a solvate. Two or three crystal forms were present. At 120°C the 5-form was produced, at 80° and 100°C, a mixture of two forms was formed and a third form was apparent at 70°C [146]. Mixtures containing two forms contained the P- and 8-form, and when three forms were present, they corresponded to the P-, 5- and s-forms. A single DTA endotherm was found in samples prepared at 100° and 120°C with an endothermic peak at 103°C, equivalent to the 5-form. Melting endotherms at 91-92°C were found for samples obtained at 70°C and 80°C. In these samples a recrystallisation exotherm at 93°C, corresponding to the 5-form was found again the 5-form subsequently melted as an endotherm at 103°C [146]. 

According to McCrone [27], in a poor solvent the rate of transformation of a metastable to a more stable polymorph is slower. Hence a metastable form once crystallized can be isolated and dried before it is converted to a more stable phase by solution phase mediated transformation. In some systems the metastable form is extremely unstable and may be prepared only with more extreme supercooling. This is usually performed on a very small scale with high boiling liquids so that a saturated solution at a high temperature that is suddenly cooled to room temperature will achieve a high degree of supersaturation [28]. 

Dehydration of hydrates can also lead to the formation of unique crystals. Caffeine Form II was prepared by recrystallizing caffeine from water, drying for 8 days at 30°C, and then heating for 4 hours at 80°C [38]. Chloroquine diphosphate 3 1 hydrate was converted to the anhydrous form at temperatures above 188°C [49]. Etoposide Form I (a monohydrate) was found to undergo a dehydration reaction in the temperature range of 85-115°C to yield etoposide Form la. This form could be melted at 198°C and transformed to etoposide Form Ila, which itself melted at 198°C and crystallized to still another polymorph, etoposide Form Ila at 206°C. Etoposide Form Ila was found to melt at 269°C and convert to its hydrated form, etoposide Form n, when exposed to the atmosphere at room temperature. This hydrate was also found to undergo a dehydration reaction at 90-120°C to yield etoposide Form Ila [50]. 

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