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Molecular interactions between water and HPMC polymers
s174
Poster Session P3: 1
Diffusion cells (Franz cells) consist of two compartments separated by a membrane are and are often used to investigate the diffusional pammeters of cornpounds. A solution of the compound is placed in the donor compartment and a liquid providing sink conditions in the receptor compartment. For most instances, aqueous receptor solutions are used. The increasing unsuitability of water as a receptor phase for a series of l-alcohols has been demonstrated. For pentanol and hexanol, the diffusion profile reached a plateau after 12hrs. which coincided with saturation of the receptor phase with the diffusant. Cosotvents or additives are often included in receptor phases to increase the solubilii of lipophilic permeants but the effect of these modified receptor media on membrane i&@ity is questionable. An alternative method for the investigation of diiusion is to monitor directly the arrival of a diffusing species at the distal membrane interface. This can be achieved by replacing the receptor solution wfth an attenuated total reflection (ATR) crystal, which is positioned on an FTIR spectrophotometer. A diffusion profile for the arriving permeant at the membrane-crystal interface can be obtained by plotting diffusant peak areas against time and, by fitting the data to the appropriate equation, diffusion coefficients (D) can be calculated. Using this method the values of D for a series of l-alcohols have been determined. Values of D decreased with increasing molecular volume, with the largest decrease occurring between methanol and propanol. The values of D for the alcohols, propanol through to decanol, were similar. These experiments have demonstrated the role of AT&FTIR spectroscopy in investigating the diffusion coefficients of a series of compounds with increasing lipophilicity when an aqueous receptor solution is not appropriate.
Hydroxypropybnethykdlulose (HPMC) polymers are commonly used in hydrophilic matrices. The initial water uptake of the polymer to form a barrier & lam and consequent water ditksion in this Bel layer are the otsjor fitctorsdetemk@dntg&asefiomtheirnuttks(1). Thepresentstudyis umcunedwiththeint~onbehveenwateraodHPMC.Atbermalat+iis tedmiqq diEkrWial Wmittg cdotimetry @SC) (2) has baen Wed to examine the nahue of this intaraction and diibotion of water within HPMC gds. HPMC (Metbocel KIN) gds (IO-W/o w/w) were prepared and stored at 4°C for 24 or 96 hours snd then scanned osing a Perkin-Elmer differentid WaMirlg &rimeter (DSC7). Characteristic tharmd events were appareot in the DSC scans of HPMC K15MgelrwhichwmfouadtobedependentoagdstonBetime.polymer concaantionandwolingandheatiqratesutikddutittgscanGg.Twoor montbarmrleventswaepreMnonthelowtempauuresideofthemelting endotherm for gds (20-35% w/w) in the region of -IS’C to 0“C. These ofdi&axtypsaofwatex(tkeaodbound eventsarerelatedtotbeprueace water) which exist in HPMC KISM gels. It was found that the monk of moles of non-lkziq (bouad) water per polymer repeat@ unit of HPMC KlSM was 11.6 moles for 24 hour samples and 3.75 moles for % hour samples. This reduction in the amotmt of bound watez per h* re+Wing unit may be doe to water beiog rdeased from the polymer during equilibration with time. 1. AR. Rajabi-Simi et al, Proc. 3rdAnn. UKapsConf (1994)21 2. J. L. Ford and K. Mitchell, Thermochim. Acta (1995) 248, 329-345
Dirent hydroxypropylmethytclluloses: Methocel A, E. K (Colorcon Ltd., Kent) and ona starchderivative(hydroxypropyl starch. Eridania Beghin-Say-Cerestar, Vilvoorde, Belgium) were evaluated for their enuWfying parties. Eight dk, emulsions vmre prepered with 20% (wti) arachiii oil (Federa. Belgium) and 80% (wAv) aqueous phase containing the emulsifying agent in different concentrations. Hydroxypropyl starch, fvbthooel KlOO-LV, Methocel ES-LV and Methocel A4C were used in a 2% (wAw) concentration, while Methocel AWLV was used in a 1%. 2%. 3% and 4% (w/w) concentWon. The stability ofthe emulsions wes assessed by three different methods: by visual inspection, by electrical conductance measurements and by droplet size measurements (Coulter Counter). The hydroxypropyl starch emulsion showed already after 3 hrs a visual instability, followed by the Methocal ASLV 1% emulsion (3 days), the 2% emulsion (6 days) and the ESO-LV emulsion (55 days). The Methocel Al5-LV 3% and 4%, the Methocel KlOO-LV (2%) emulsion and the A4C (2%) emulsion showed no visual instability after 60 days. The difference in electricel condudance between the upper and lower part of the oonductence call, especially designed for the stability study, gradually increased while aging. Droplet size measurements showed no major differences in droplet sizes in functionof time, pmbabtydw to the fact that before measurements the emulsions had to be gently shaken before sample taking. Conclusion of this study is that the electrical conductance measurements in the specially designed cells can be used to quantify and predict the phase separation in o&emulsions. To producean emulsion (ti 20180) of accqztable stability, Methocel KlOO-LV, ESO-LV and A4C should be used in a 2% (w/w) concentration and h4ethocelAl 5-LV should be used in a 3 or 4% (wkw) concentmtion.
Hydroxypropyl methylcellulose (HPMC) is used in oral controlled release (CR) matrix tablet formulations and controls drug diffusion and tablet erosion by forming a gel layer at the tablet surface. The CR characteristics of HPMC may be altered if its ability to hydrate is modified by additives such as buffers and salts, present in dissolution media. Oscillation rheology techniques were used to determine the gelation temperature (GT) of HPMC E4M gel, and the effect of various additives on the GT. A concentration dependent reduction in the GT, associated with HPMC dehydration, was caused by KH,PO,, NaCl and lactose. The magnitude of reduction was also dependent on the additive used, KH,PO, having the greatest effect. The GT data was used to explain the effect of dissolution media additives on the release profile of a model drug (fluconazole), from HPMC E4M matrix tablets. Their effect on fluconazole release rate was also concentration dependent, though a linear response was not observed. As the additive concentration increased, the release Further rate was reduced until a minimum was achieved. increases in additive concentration ultimately resulted in failure of the matrix tablet and “dose dumping”. The initial retardation of release rate was probably due to a reduction in fluconazole diffusion as a result of increased matrix tortuosity. The enhanced release rate observed at higher additive concentrations was due to an increase in the erosional release of fluconazole probably as a consequence of a reduction in gel layer viscosity. It can be concluded that when the GT of HPMC is altered by an additive, this is a good indication that the CR characteristics of a matrix tablet may be modified when this additive is present in the In addition this rheological technique is dissolution media. considered suitable for assessing the ability of drugs, and CR matrix tablet excipients to influence HPMC hydration and CR properties.
Poster Session P3: 1
Diffusion cells (Franz cells) consist of two compartments separated by a membrane are and are often used to investigate the diffusional pammeters of cornpounds. A solution of the compound is placed in the donor compartment and a liquid providing sink conditions in the receptor compartment. For most instances, aqueous receptor solutions are used. The increasing unsuitability of water as a receptor phase for a series of l-alcohols has been demonstrated. For pentanol and hexanol, the diffusion profile reached a plateau after 12hrs. which coincided with saturation of the receptor phase with the diffusant. Cosotvents or additives are often included in receptor phases to increase the solubilii of lipophilic permeants but the effect of these modified receptor media on membrane i&@ity is questionable. An alternative method for the investigation of diiusion is to monitor directly the arrival of a diffusing species at the distal membrane interface. This can be achieved by replacing the receptor solution wfth an attenuated total reflection (ATR) crystal, which is positioned on an FTIR spectrophotometer. A diffusion profile for the arriving permeant at the membrane-crystal interface can be obtained by plotting diffusant peak areas against time and, by fitting the data to the appropriate equation, diffusion coefficients (D) can be calculated. Using this method the values of D for a series of l-alcohols have been determined. Values of D decreased with increasing molecular volume, with the largest decrease occurring between methanol and propanol. The values of D for the alcohols, propanol through to decanol, were similar. These experiments have demonstrated the role of AT&FTIR spectroscopy in investigating the diffusion coefficients of a series of compounds with increasing lipophilicity when an aqueous receptor solution is not appropriate.
Hydroxypropybnethykdlulose (HPMC) polymers are commonly used in hydrophilic matrices. The initial water uptake of the polymer to form a barrier & lam and consequent water ditksion in this Bel layer are the otsjor fitctorsdetemk@dntg&asefiomtheirnuttks(1). Thepresentstudyis umcunedwiththeint~onbehveenwateraodHPMC.Atbermalat+iis tedmiqq diEkrWial Wmittg cdotimetry @SC) (2) has baen Wed to examine the nahue of this intaraction and diibotion of water within HPMC gds. HPMC (Metbocel KIN) gds (IO-W/o w/w) were prepared and stored at 4°C for 24 or 96 hours snd then scanned osing a Perkin-Elmer differentid WaMirlg &rimeter (DSC7). Characteristic tharmd events were appareot in the DSC scans of HPMC K15MgelrwhichwmfouadtobedependentoagdstonBetime.polymer concaantionandwolingandheatiqratesutikddutittgscanGg.Twoor montbarmrleventswaepreMnonthelowtempauuresideofthemelting endotherm for gds (20-35% w/w) in the region of -IS’C to 0“C. These ofdi&axtypsaofwatex(tkeaodbound eventsarerelatedtotbeprueace water) which exist in HPMC KISM gels. It was found that the monk of moles of non-lkziq (bouad) water per polymer repeat@ unit of HPMC KlSM was 11.6 moles for 24 hour samples and 3.75 moles for % hour samples. This reduction in the amotmt of bound watez per h* re+Wing unit may be doe to water beiog rdeased from the polymer during equilibration with time. 1. AR. Rajabi-Simi et al, Proc. 3rdAnn. UKapsConf (1994)21 2. J. L. Ford and K. Mitchell, Thermochim. Acta (1995) 248, 329-345
Dirent hydroxypropylmethytclluloses: Methocel A, E. K (Colorcon Ltd., Kent) and ona starchderivative(hydroxypropyl starch. Eridania Beghin-Say-Cerestar, Vilvoorde, Belgium) were evaluated for their enuWfying parties. Eight dk, emulsions vmre prepered with 20% (wti) arachiii oil (Federa. Belgium) and 80% (wAv) aqueous phase containing the emulsifying agent in different concentrations. Hydroxypropyl starch, fvbthooel KlOO-LV, Methocel ES-LV and Methocel A4C were used in a 2% (wAw) concentration, while Methocel AWLV was used in a 1%. 2%. 3% and 4% (w/w) concentWon. The stability ofthe emulsions wes assessed by three different methods: by visual inspection, by electrical conductance measurements and by droplet size measurements (Coulter Counter). The hydroxypropyl starch emulsion showed already after 3 hrs a visual instability, followed by the Methocal ASLV 1% emulsion (3 days), the 2% emulsion (6 days) and the ESO-LV emulsion (55 days). The Methocel Al5-LV 3% and 4%, the Methocel KlOO-LV (2%) emulsion and the A4C (2%) emulsion showed no visual instability after 60 days. The difference in electricel condudance between the upper and lower part of the oonductence call, especially designed for the stability study, gradually increased while aging. Droplet size measurements showed no major differences in droplet sizes in functionof time, pmbabtydw to the fact that before measurements the emulsions had to be gently shaken before sample taking. Conclusion of this study is that the electrical conductance measurements in the specially designed cells can be used to quantify and predict the phase separation in o&emulsions. To producean emulsion (ti 20180) of accqztable stability, Methocel KlOO-LV, ESO-LV and A4C should be used in a 2% (w/w) concentration and h4ethocelAl 5-LV should be used in a 3 or 4% (wkw) concentmtion.
Hydroxypropyl methylcellulose (HPMC) is used in oral controlled release (CR) matrix tablet formulations and controls drug diffusion and tablet erosion by forming a gel layer at the tablet surface. The CR characteristics of HPMC may be altered if its ability to hydrate is modified by additives such as buffers and salts, present in dissolution media. Oscillation rheology techniques were used to determine the gelation temperature (GT) of HPMC E4M gel, and the effect of various additives on the GT. A concentration dependent reduction in the GT, associated with HPMC dehydration, was caused by KH,PO,, NaCl and lactose. The magnitude of reduction was also dependent on the additive used, KH,PO, having the greatest effect. The GT data was used to explain the effect of dissolution media additives on the release profile of a model drug (fluconazole), from HPMC E4M matrix tablets. Their effect on fluconazole release rate was also concentration dependent, though a linear response was not observed. As the additive concentration increased, the release Further rate was reduced until a minimum was achieved. increases in additive concentration ultimately resulted in failure of the matrix tablet and “dose dumping”. The initial retardation of release rate was probably due to a reduction in fluconazole diffusion as a result of increased matrix tortuosity. The enhanced release rate observed at higher additive concentrations was due to an increase in the erosional release of fluconazole probably as a consequence of a reduction in gel layer viscosity. It can be concluded that when the GT of HPMC is altered by an additive, this is a good indication that the CR characteristics of a matrix tablet may be modified when this additive is present in the In addition this rheological technique is dissolution media. considered suitable for assessing the ability of drugs, and CR matrix tablet excipients to influence HPMC hydration and CR properties.