Chapter 2. Material and Methods
3.3. Results
3.3.2. Preparation of HME PVP-based SDs
3.3.2.1. HME parameter investigation: Extrusion temperature
Before the extrusion of an HME formulation, it is important to understand the thermal properties of the raw materials in order to avoid the inappropriate use of processing parameters (such as high extrusion temperature and long residence time of extrusion). To do this, TGA was used to measure the degradation temperature and water content (%) of the raw materials. On the other hand, DSC was used to measure the Tm or Tg of the drug and polymer, respectively. Table 3.6 lists the thermal properties of the raw materials from both DSC and TGA analysis.
Table 3.6: Thermal properties of raw materials from DSC and TGA analysis Compounds Melting (Tm)/ Tg
temperature (oC)
Degradation
temperature (oC) Water content (%)
PCM Tm=169-172 199.1 ± 9.1 0.12 ± 0.14
CAF Tm=231-234 172.4 ± 6.7 0.15 ± 0.06
PVP K29-32 Tg=164 177.6 ± 1.7 5.53 ± 0.94
PVPVA 6:4 Tg=106 282.1 ± 2.3 3.97 ± 0.91
It is interesting to note that an apparent weight loss was seen for raw CAF powder well below the reported melting temperature (Table 3.6). This is ascribed to the sublimation of CAF molecule at a temperature around ≈ 175 oC (Moura Ramos et al., 2006).
The water contents for both the crystalline PCM and CAF are almost negligible. In contrast, the water content of homopolymer was noted to be relatively high as compared to PVPVA 6:4. This is due to the hygroscopic nature of the PVP (Callahan et al., 1982). The relationship between the water content of the raw material and the extrudates will be further commented on in a later section (Chapter 3.3.3.1).
To determine an appropriate extrusion temperature, HSM was used to identify the fusion temperature of the drug and polymer. The purpose of identifying the fusion temperature, a temperature which leads to the liquid state formation of the mixture, is to anticipate an appropriate extrusion temperature that will ease the flowability of the mixture in the HME barrel while processing. It should be emphasized that the fusion temperature here refers to a temperature that causes the transformation of the solid state of the mixture to a liquid or fluidized state. Thus, it may not necessary be equivalent to the Tm or Tg of the drug and polymer, respectively. Figure 3.5 (I) to (IV) show images of the 50% API-polymer physical mixture which were captured during heating.
Preparation and characterization of HME PVP-based solid dispersions Chapter 3
School of Pharmacy, University of East Anglia 105
Figure 3.5: HSM screens of PM of 50% API-polymers. I) Fusion of PCM- PVP K29-32 at T ≈ 140 oC, II) Fusion of PCM- PVPVA 6:4 at T ≈ 130 oC, III) Fusion of CAF- PVP K29-32 at T ≈ 180 oC, and IV) Fusion of CAF- PVPVA 6:4 at T ≈ 175 oC. Figures on the left which is denoted as (a) are screens captured before the apparent fusion was noted and figures on the right which is denoted as (b) are screens captured when the fusion event was clearly seen.
I (a)
II (a)
≈ 140oC
≈ 130oC
≈ 180oC
≈ 175oC I (b)
II (b)
III (a) III (b)
IV (a) IV (b)
Preparation and characterization of HME PVP-based solid dispersions Chapter 3
School of Pharmacy, University of East Anglia 106
The fusion temperature between the PCM and PVP K29-32 (Figure 3.5 I (a) and (b)) occurs at a temperature well below (i.e. circa 140 oC) the Tm and Tg of the PCM and PVP K29-32, respectively. The depressed temperature is in good agreement to the melting point depression data obtained previously in the DSC scan (Figure 3.2). It may therefore be expected that the extrusion of PCM in PVP K29-32 could be performed at lower temperatures than their individual thermal properties would indicate.
On the other hand, the fusion temperature between the PCM and PVPVA 6:4 occurred at temperature around 130 oC in the presence of PVPVA 6:4 (Figure 3.5 II (a) and (b)). This is due to the low Tg of PVPVA 6:4 leading to its softening below the melting of PCM and, subsequently, the dissolution of PCM into the softened PVPVA 6:4. Thus, it was also expected that this mixture could also be extruded at temperatures lower than the melting point of PCM.
HSM screens of the PM CAF-PVP carriers also show lower fusion temperatures i.e. ≈ 180 oC and ≈ 175 oC for PM CAF PVP K29-32 and PM CAF PVPVA 6:4, respectively. Both temperatures were below the Tm of the drug (Figure 3.5 (III) and (IV)). However, due to the low degradation temperature of PVP K29-32 (i.e. 180 oC from TGA data) it was thus expected that extrusion of the CAF PVP K29-32 needed to be performed at a lower temperature than 180 oC, whereas mixture of CAF PVPVA 6:4 could be extruded at 180 oC as the polymer degradation temperature is > 200 oC.
The extrusion of PCM PVPs and CAF PVPs
Previous studies have indicated that the extrusion processes may be performed at temperatures below the melting point of PCM due to the melting point depression of the PCM in the presence of PVP polymers. Thus, HME PCM-PVPs extrudates was prepared using an extrusion temperature of 120 oC. Clear extrudates were obtained up to 40% and 50% of PCM PVPVA 6:4 and PCM PVP K29-32 system, respectively. On the other hand, only 10% and 20% caffeine loading produced clear extrudates for PVPVA 6:4 and PVP K29-32, respectively. However, it should be emphasized that the extrusion of 10% HME PVP based extrudates was difficult as a low yield and high value of processing torque was noted. This is ascribed to the insufficient plasticization of the small fraction of API to the high fraction of PVP polymers which causes high viscosity of the resultant molten system.
Figure 3.6 illustrates the example of HME 20 to 70% PCM and PVP K29-32 extrudates that had been prepared at 120 oC. It was suspected that the extrudates with an opaque appearance provided evidence of incomplete drug solubilisation, while the transparent extrudates showed complete solubilisation of the drug. However, further investigation was needed to confirm the amorphicity of the clear extrudates.
Preparation and characterization of HME PVP-based solid dispersions Chapter 3
School of Pharmacy, University of East Anglia 107
Figure 3.6: Appearance of extrudates of HME 20 - 70% PCM-PVP K29-32 prepared at 120 oC