X Ray Diffractometry

It is well known that Theophylline exists either as anhydrate or monohydrate. Theophylline anhydrate has two polymorphic forms, form II which is stable at room temperature and form I which is stable at high temperatures (see chapter 2.5). In

Results and Discussion order to characterize polymorphic and pseudo polymorphic forms and check the influence of roller compaction, milling and tableting to polymorphic/pseudo polymorphic forms X-ray powder diffractometry was applied. The same measurement was done with powder and granules and results were compared.

X-ray powder and granules diffraction patterns were significantly different for the monohydrate and anhydrous form (see figure 5.18, figure 5.19 and figure 5.20) and

equivalent to those presented in the literature 49. THAP powder and granules

produced by roller compaction at pressure of 20 and 30 bars showed characteristics peaks for Theophylline anhydrate form II which is stable at room temperature.

Figure 5.18.: X-ray diffraction patterns of THAP powder (upper), granules produced at pressure of 20 bars (middle) and granules produced at pressure of 30 bars (lower) Diffraction pattern of THAP showed characteristic peaks of the stable anhydrous Theophylline (form II) at 7.2, 12.6 and 14.5° 2θ. These characteristic peaks are in agreement with results previously presented in the literature by Airaksinen et al.

2004,49 _{Phadnis and Suryanarayanan 1997,}45 _{have described an anhydrous}

metastable form of Theophylline that has a different X – ray diffraction pattern, with characteristics peaks at 9.4, 11.3, 12.4,13.5 and 15.4° 2θ.

InFigure 5.18 it could be observed that diffraction patterns of THAP granules (20 and 30 bars) were not changed comparing to THAP powder. Since the diffraction pattern of THAP remained unchanged after roller compaction it could be noticed that roller compaction did not have any influence on the polymorphic form.

Figure 5.19.: X-ray diffraction patterns of THAFP powder (upper) and granules produced at pressure of 20 bars (lower)

THAFP is the anhydrous form II as well, what could be confirmed by diffraction pattern presented in Figure 5.19. It showed the same characteristic peaks like THAP at 7.2, 12.6 and 14.5° 2θ. After roller compaction diffraction was unmodified, so it indicated that roller compaction had no influence on the polymorphic form of THAFP.

Results and Discussion

Figure 5.20.: X-ray diffraction patterns of THMO powder (upper) and granules produced at 20 bars (lower)

The X – ray diffraction pattern of THMO was in agreement with that previously presented in the literature 49 _{with characteristics peaks at 8.8, 11.5, 13.3 and 14.7 2θ.} In figure 34 it is shown that roller compaction did not have any influence on the diffraction pattern, what implicate that pseudo polymorphic form of THMO was also not changed.

In the chapter 2.5 the way of dehydration of Theophylline monohydrate is shown as a function of temperature (see figure 2.16). This could occur even during compaction under high pressure. However, figure 5.20 confirmed that after roller compaction and milling it still existed as monohydrate.

5.4.4. Differential Scanning Calorimetry (DSC)

Results of DSC measurement of THAP, THAFP and THMO granules are presented together with the results obtained for powder, compacts and tablets, see chapter 5.5.1.

5.5. Tablet Characterization

5.5.1. Differential Scanning Calorimetry (DSC

)

In order to check the influence of roller compaction and milling on the structure and polymorphic forms of Theophylline, DSC measurement of pure powders (THAP, THAFP and THMO), ribbons, granules and tablets were performed.

Figure 5.21.: .DSC thermogram of THAP, powder, ribbon, granules and tablet (20bar) According to European Pharmacopoeia melting point of Theophylline is 270 - 274°C. Suzuki et al. 1989,43 _{prepared separately two polymorphic forms of Theophylline} (form II and form I) and made their careful thermochemical analysis. They showed that DSC measurement of these two forms gave different results: form II had a melting point at 273.4 ± 1.0°C and form I at 269.1 ± 0.4°C. Phadnis and Suryanaranyanan 1997, 45 _{showed that stable form II had a melting point at 271°C.} THAP original powder used in this study showed an endothermic peak at 271.0 ± 0.5°C and enthalpy 157.2 ± 3.2 J/g; ribbons produced at pressure of 20 bars had the

Results and Discussion same peak at 272.0 ± 0, 2°C and enthalpy of 152.1 ± 2.2 J/g; granules obtained from these ribbons had a peak at 271.9 ± 0.3°C, enthalpy of 153.8 ± 3.3 J/g, and tablets of 12% porosity had a peak at 271.7 ± 0.2°C and enthalpy of 156.0 ± 6.5 J/g. The thermograms of THAP powder, ribbon, granules and tablets are presented in figure 5.22.

Figure 5.22.: DSC thermogram of THAFP, powder, ribbon, granules and tablet

Analogue to the THAP, THAFP showed the same endothermic peak which is due to the melting point of the material. THAFP pure powder, ribbons, granules and tablets showed peak and enthalpy as follows: 271.3 ± 0.2°C and enthalpy of 162.8 ± 3.4J/g, 271.1 ± 0.1°C and enthalpy of 160.2 ± 1.5 J/g, 271.1 ± 0.1°C and enthalpy of 161.761 ± 6.3 J/g and 271.4 ± 0.2°C and enthalpy of 154.6 J/g, respectively. These results showed that there was no conversion of the polymorphic form during roller compaction and milling.

Figure 5.23.: DSC thermogram of THMO, powder, ribbon, granules and tablet

THMO showed first endothermic wide peak around 60 – 80°C due to dehydration and transition of hydrate to anhydrate, second endothermic sharp peak is due to melting of anhydrate. Suzuki et al.1989 43_{, showed that a dehydration of Theophylline} monohydrate to anhydrate is at 71°C and further melting of stable anhydrate form is at 273°C.

THMO original powder, used in this study, showed first wide peak and enthalpy at 72.9 ± 2.2°C, 186.1 ± 14.6 J/g and second sharp peak end enthalpy at 271.8 ± 0.2°C, 149.4 ± 1.8 J/g. Ribbons produced by roller compaction at pressure of 20 bars showed these peaks at 75.1 ± 1.0°C, enthalpy of 165.9 ± 10.3 J/g, and 271.6 ± 0.2°C, enthalpy of 146.9 ± 6.4 J/g. In the case of granules peak of dehydration was at 76.0 ± 0.7°C, enthalpy of this peak was 170.2 ± 4.3 J/g, and peak of melting point at 271.6 ± 0.2°C and enthalpy of 147.0 ± 0.1 J/g. THMO tablets produced from granules obtained by roller compaction had peak at 73.3 ± 0.3°C, enthalpy of this peak was 164.2 ± 3.2 J/g. Second sharp peak which corresponded to the melting was at 270.6 ± 0.1°C and enthalpy was 140.5 ± 2.4 J/g

Results and Discussion

Figure 5.24.: DSC thermogram of THAP, powder, ribbon, granules and tablet (30bar)

THAP compacted at pressure of 30 bars had the same melting point as THAP compacted at pressure of 20 bars, which led to the conclusion that increasing the pressure of compaction did not change the polymorphic form of Theophylline anhydrate. Melting point of THAP ribbons produced at pressure of 30 bars was at 271.2 ± 0.1˚C; enthalpy was 153.8 ± 1.2 J/g. Granules had the endothermic peak at 271.0 ± 0.5˚C and enthalpy of this peak was 133.7 ± 2.5 J/g, and tablet had the same peak at 271.2 ± 1.2˚C with enthalpy 146.7 ± 3.5 J/g.