Case Histories - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 172

Figure 4 DSC heating scans of formulated and freeze-dried CGRP (for details, see text).
The first scan shows T g , followed by an irruptive crystallisation of the stabiliser
(lactose). The resulting product was recooled to 501C and reheated. The scan
shows a characteristic ice melting endotherm. Data from unpublished Pafra
Biopreservation studies
changes. In the preparation under test, such heating resulted in a sudden
lactose crystallisation, leaving an amorphous product phase of 40%
CGRP and 60% ''residual'' water. This is shown dramatically by the
narrow, intense exotherm, representing the heat of lactose crystallisation
in Scan 1 of Figure 4. The sample was cooled down to 501C, annealed
and rescanned (Scan 2). This scan shows no evidence of a glass transi-
tion but an ice melting endotherm, as typically observed for frozen
solutions above their T g . The sudden removal of the excipient by its
crystallisation had thus left a residual (now dilute) CGRP/water solu-
tion with a subzero T g , evidently below 501C, rendering it unstable at
ambient temperature. The broad endotherm is characteristic of ice
melting into a concentrated solution.
12.8 Summary and Conclusions
The problems encountered and their resolution graphically illustrate the
major impact made by changes of composition and fill depth on a
previously optimised drying cycle, neglect or ignorance of which will
almost invariably end in disaster. Since the practical freeze-drying
activities and experiences of Pafra Biopreservation were largely confined
to problem solving for individual client companies, we only saw ''hos-
pital cases'', in the words of our Technical Manager. Nevertheless, from