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Thermal behaviour of dihydrates prepared from carbamazephine polymorphism
S182
Poster Session P3: Tuesday I7 September
2-[[[3-meth~-4-(2,2,2-trifluoroeMoxy)-2-pyridyI]me~~]sulfinyl]-l Hbenzimidazole is a novel antiulcer drug which acts as a proton pump inhibitor. Two polymorphs and more pseudopolymorphs were prepared and characterized by differential scanning calorimetry (DSC). X-ray powder difractometry and optical microphotographs. The results showed significant differences between them. The purpose of our work was also the study of the physical stability of two polymorphic forms designated as A and 8. DSC curve of the form A showed only an endothermic peak at 18O”C, while the form B showed one exothermic peak at 102°C and one endothermic peak at lEO”C, indicating that the form 6 undergoes solid-solid transition to the form A. It was proved that form B is unstable and is completely converted to the stable form A under physical stress (mulling) or if staying for some time at ambient temperature.
Anhydrous carbamazepine (CBZ) will rapidly tranform to a dihydrate when dispersed in water (1). The formation of clkfarent crystal CBZ forms upon removal of hydrate water has been reported (2,3). This study has examined the thermal properties of CBZ dihydrates prepared horn two CBZ polymorphs, form Ill (DIHIII) and form I (DIHI). Isothermal TGA analysii was performed on the dihydrates at 25°C. DSC sturfiis ware carriad out from 26200°C at a heating rate of 20°C min” with samples in sealed, pierced pans. FT-Raman (FTR) spectra were obtained on a BNker IFS-66 FT Raman module. 200 scans at 4cm” resolution from 50_35OOcm-’ were collected. Onfy small differences were cbserved in the rate of water loss from both dihydrates heated in the TGA, suggesting water molecules are similarly held within the dihydrata fattii. FTR analysis showed dehydrated samples to have spectra consistent with form I (4). DSC analysis, however, indicated subtks differences in the two dihydrates. After water removal, which occurred from 6090°C in both dihydrates. DIHI exhibited only the form I melting endothen at 190°C. whereas DIHIII displayed an additional endotherm at IWC, which is the CBZ form III to form I conversion temperature. FTR studies of samples remov_edfrom the DSC pan at 1WC, showed DIHI material was consistent tii form I, whereas the spectra of DIHIII was consistent with form III. The data suggest that CBZ dihydrates have different physical properties that are manifest upon dehydration under elevated local humidity conditions, such as in the DSC pans. One expbnantion is that a small undetected amount of anhydrous polymorphic form exists which acts to seed the dehydration process under favourabie humidity conditions. I. Ycung,W.L.L. 8 Suryanarayanan, R., J.Pharm.Sci.. 1991,88,49&500 2. Dugua, J. eta/, Pharm.Ada.Helv.. 1991. SE, 307-310 3. Han, J, 8 Suryanatayanan, R., Phann.Ras., 1995, 12 (SuppI.). S-141 4. McMahon ef a/, ICORS Conference Proceedings, Wiley, Chichester,
1994, pp908909
increased benefits from a number of drugs aWkt be gained if formulated as a gastroretentii dosage form. Examples indude drugs with a narrow
therapeutic window, e.g. fnrsemide. and any agents acting topicaky on the gastric mucosa, e.g. dNgS to era&ate Helicobacter pytorf. There are several approaches to achieve such fcnnulations. In this study, we have developad a muftiple-unk ftcating dosage fon manufa&ured from cakium alginate (CaA) gel spheres. Algtnatas are nontoxic bbqk copolymer marides found in brown se-s and are widely used in the food and pharmacautical industries. The beads are formad by dropping a sodium atginate solution (N&I) into aqueous calcium chloride (Car&), which prosclinks predominantlywtth one of the monomer blocks to form an ‘egg-box modal’of insotubiaCaA (Thorn et al, 1982). Several parameters in the manufacture of the beads were assessad with respad to effect on floating properties. Thase ware drying methods, NaA and CaCls amcantratkms. neadie gauge, dropping heights and wing times. Using an optimised formutatin wkh snap-fraezing in liquid Nz, followed by freeze-drying at 40% for 24 hours, spherical beads of approximataty 2.5 mm in diameter ware produced, which floated on agitated acidic media (O.lM HCI + 0.05% Tween 80) for over 12 hours. Further testing was carried out using the resultant-weight apparatus of Timmermans 8 M&s (1990) whit provides a more accurate measure of floating ability, and confirmed that, although the units did not swell, they maintainad a pnsitii floating-force ovar thii period. Scanning electron microscopy (SEM) and environmental SEM (ESEM) were used to charactertse the beads. The outer surfaqas were continuous and nonporous and pores were not observed as the surface of the bead became hydrated. The inner structure consisted of a channelted network of CaA. Denslty measurements, performed using a helium pymometer. gave results of less than 1 gun-‘. In conduskm. freeze-dried CaA baads show interesting potential as a gastroretentive dosage form and warrant further investigation with
Usually pellets obtained from extrusion/ spheronization do not tend to disintegrate. However it was possible to produce disintegrating pellets by using a combination of a suitable disintegrant with a granulation liquid containing a high fraction of 2-propanol 111. The reduction of water necessary for extrusion was thought to be a main reason for the disintegration. The tested formulation contained 60% of microcrystalline cellulose (WC). The aim of this study was to prove this hypothesis by reducing the water content by different means: a partial substitution of MCC by either a non water soluble excipient such as dicalciumphosphate dihydrate (DCPD) or by a soluble one such as mannitol should result in a reduction of total granulation liquid. In combination with different fractions of 2propanol four series of experiments were performed: formulations containing sodium starch glycolate (10% (w/w)) as disintegrant, propyphenazone (30%) as a model drug, MCC (20 or40%) and excipient (20 or 40%) were extruded in a power-consumption-controlled extruder and tested for their disintegration and dissolution behaviour. It was possible to reduce the water content during extrusion by the partial substitution of MCC. The soluble mannitol led to lower water contents during extrusion compared to the insoluble DCPD. Both disintegration and dissolution were enhanced by lower water contents. With 40% mannitol k was possible to produce disintegrating pellets without 2-propanol. This supports the hypothesis that it is the water content in the extrudate which is relevant for disintegration rather than the composition of the granulation liquid or the total amount of the granulation liquid.
inWrpoNted dN9S. Thorn D et al. Garb. Researchjgg (1982) 2942 TimmermansJ, MO& Al. Int. J. Pharm. S;r (1990) 207-216
[I ]
M. Schr&.fer and P. Kleinebudde. Phanaceutical Sciences 1 (1995) 415418
Poster Session P3: Tuesday I7 September
2-[[[3-meth~-4-(2,2,2-trifluoroeMoxy)-2-pyridyI]me~~]sulfinyl]-l Hbenzimidazole is a novel antiulcer drug which acts as a proton pump inhibitor. Two polymorphs and more pseudopolymorphs were prepared and characterized by differential scanning calorimetry (DSC). X-ray powder difractometry and optical microphotographs. The results showed significant differences between them. The purpose of our work was also the study of the physical stability of two polymorphic forms designated as A and 8. DSC curve of the form A showed only an endothermic peak at 18O”C, while the form B showed one exothermic peak at 102°C and one endothermic peak at lEO”C, indicating that the form 6 undergoes solid-solid transition to the form A. It was proved that form B is unstable and is completely converted to the stable form A under physical stress (mulling) or if staying for some time at ambient temperature.
Anhydrous carbamazepine (CBZ) will rapidly tranform to a dihydrate when dispersed in water (1). The formation of clkfarent crystal CBZ forms upon removal of hydrate water has been reported (2,3). This study has examined the thermal properties of CBZ dihydrates prepared horn two CBZ polymorphs, form Ill (DIHIII) and form I (DIHI). Isothermal TGA analysii was performed on the dihydrates at 25°C. DSC sturfiis ware carriad out from 26200°C at a heating rate of 20°C min” with samples in sealed, pierced pans. FT-Raman (FTR) spectra were obtained on a BNker IFS-66 FT Raman module. 200 scans at 4cm” resolution from 50_35OOcm-’ were collected. Onfy small differences were cbserved in the rate of water loss from both dihydrates heated in the TGA, suggesting water molecules are similarly held within the dihydrata fattii. FTR analysis showed dehydrated samples to have spectra consistent with form I (4). DSC analysis, however, indicated subtks differences in the two dihydrates. After water removal, which occurred from 6090°C in both dihydrates. DIHI exhibited only the form I melting endothen at 190°C. whereas DIHIII displayed an additional endotherm at IWC, which is the CBZ form III to form I conversion temperature. FTR studies of samples remov_edfrom the DSC pan at 1WC, showed DIHI material was consistent tii form I, whereas the spectra of DIHIII was consistent with form III. The data suggest that CBZ dihydrates have different physical properties that are manifest upon dehydration under elevated local humidity conditions, such as in the DSC pans. One expbnantion is that a small undetected amount of anhydrous polymorphic form exists which acts to seed the dehydration process under favourabie humidity conditions. I. Ycung,W.L.L. 8 Suryanarayanan, R., J.Pharm.Sci.. 1991,88,49&500 2. Dugua, J. eta/, Pharm.Ada.Helv.. 1991. SE, 307-310 3. Han, J, 8 Suryanatayanan, R., Phann.Ras., 1995, 12 (SuppI.). S-141 4. McMahon ef a/, ICORS Conference Proceedings, Wiley, Chichester,
1994, pp908909
increased benefits from a number of drugs aWkt be gained if formulated as a gastroretentii dosage form. Examples indude drugs with a narrow
therapeutic window, e.g. fnrsemide. and any agents acting topicaky on the gastric mucosa, e.g. dNgS to era&ate Helicobacter pytorf. There are several approaches to achieve such fcnnulations. In this study, we have developad a muftiple-unk ftcating dosage fon manufa&ured from cakium alginate (CaA) gel spheres. Algtnatas are nontoxic bbqk copolymer marides found in brown se-s and are widely used in the food and pharmacautical industries. The beads are formad by dropping a sodium atginate solution (N&I) into aqueous calcium chloride (Car&), which prosclinks predominantlywtth one of the monomer blocks to form an ‘egg-box modal’of insotubiaCaA (Thorn et al, 1982). Several parameters in the manufacture of the beads were assessad with respad to effect on floating properties. Thase ware drying methods, NaA and CaCls amcantratkms. neadie gauge, dropping heights and wing times. Using an optimised formutatin wkh snap-fraezing in liquid Nz, followed by freeze-drying at 40% for 24 hours, spherical beads of approximataty 2.5 mm in diameter ware produced, which floated on agitated acidic media (O.lM HCI + 0.05% Tween 80) for over 12 hours. Further testing was carried out using the resultant-weight apparatus of Timmermans 8 M&s (1990) whit provides a more accurate measure of floating ability, and confirmed that, although the units did not swell, they maintainad a pnsitii floating-force ovar thii period. Scanning electron microscopy (SEM) and environmental SEM (ESEM) were used to charactertse the beads. The outer surfaqas were continuous and nonporous and pores were not observed as the surface of the bead became hydrated. The inner structure consisted of a channelted network of CaA. Denslty measurements, performed using a helium pymometer. gave results of less than 1 gun-‘. In conduskm. freeze-dried CaA baads show interesting potential as a gastroretentive dosage form and warrant further investigation with
Usually pellets obtained from extrusion/ spheronization do not tend to disintegrate. However it was possible to produce disintegrating pellets by using a combination of a suitable disintegrant with a granulation liquid containing a high fraction of 2-propanol 111. The reduction of water necessary for extrusion was thought to be a main reason for the disintegration. The tested formulation contained 60% of microcrystalline cellulose (WC). The aim of this study was to prove this hypothesis by reducing the water content by different means: a partial substitution of MCC by either a non water soluble excipient such as dicalciumphosphate dihydrate (DCPD) or by a soluble one such as mannitol should result in a reduction of total granulation liquid. In combination with different fractions of 2propanol four series of experiments were performed: formulations containing sodium starch glycolate (10% (w/w)) as disintegrant, propyphenazone (30%) as a model drug, MCC (20 or40%) and excipient (20 or 40%) were extruded in a power-consumption-controlled extruder and tested for their disintegration and dissolution behaviour. It was possible to reduce the water content during extrusion by the partial substitution of MCC. The soluble mannitol led to lower water contents during extrusion compared to the insoluble DCPD. Both disintegration and dissolution were enhanced by lower water contents. With 40% mannitol k was possible to produce disintegrating pellets without 2-propanol. This supports the hypothesis that it is the water content in the extrudate which is relevant for disintegration rather than the composition of the granulation liquid or the total amount of the granulation liquid.
inWrpoNted dN9S. Thorn D et al. Garb. Researchjgg (1982) 2942 TimmermansJ, MO& Al. Int. J. Pharm. S;r (1990) 207-216
[I ]
M. Schr&.fer and P. Kleinebudde. Phanaceutical Sciences 1 (1995) 415418