Poster Modeling the Process-Induced Phase … · Modeling the Process-Induced Phase Transformation...
1
Modeling the Process-Induced Phase Transformation of Indomethacin during the Melt Granulation process on Hot Melt Extruder Ting Xu 1 , Kenneth R. Morris 2 , Rutesh H. Dave 3 1 Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, NY, USA 2 Lachman Institute for Pharmaceutical Research, Long Island University, NY, USA 3 Natoli Institute for Industrial Pharmacy Research and Development, Long Island University, NY, USA PURPOSE As an emerging platform for granulation, the twin-screw extrusion has various advantages over other techniques as it’s a continuous and solvent-free process and has higher efficiency in mixing and temperature control. In our study, the possible solid form changes during the granulation processes of a metastable form Indomethacin (IMC) were monitored and controlled by evaluating the effect of various forms and intensities of stresses which are experienced by the drug. Possible transitions in response to these are identified and model based design spaces are developed in order to control the final dosage form performance. CONCLUSION(S) • A continuous melt granulation method for an indomethacin-PEG 3350 formulation was developed on a Steer hot melt extruder. A design space was established with varying processing parameters in order to understand and control the possible solid state transformations of the API during this process. The results show that under processing stresses the extent of transition as well as the transformation routes occurred and can be controlled. The relative contribution of shear stress and temperatures induced the amorphization/disordering and/or a polymorphic transformation was examined and showed temperature to be the most critical process parameter. • Careful control of the processing parameters was required in order to achieve the desired granule properties and dissolution characteristics and the basis for developing a design space for production and scale-up. RESULT(S) • The XRPD quantitation method was built around normalized measured reference patterns for the indomethacin solid phases and PEG 3350. The scale factors for each of the normalized reference patterns were optimized using the Excel Solver (GRG nonlinear) function to minimize the difference between calculated and measured XRPD data. All measured and reference data used in the method were collected under the same conditions and were initially background subtracted to remove the instrumental contribution and subsequently normalized to give a constant integrated intensity. For each unknown data set, a model powder pattern was calculated by a linear combination of data from the reference patterns. The magnitude of each reference pattern in the linear combination was adjusted by a scale factor. To allow for sample displacement errors, a variable angular offset was included in the model calculation. By adjusting the individual scale factors and the angular offset, the Excel Solver (GRG nonlinear) function minimized the difference between the calculated model data and unknown data. The returned scale factors were used as quantitative measures of the concentration of each phase in the unknown material. • A continuous process which can combine two sequential stages (melting and mixing, and cooling) was employed to manufacture granules in this study. The basis of a design space was developed by setting the input variables (temperature at each functioning zone and size/design of kneading blocks on each screw) and monitoring the resulting product to assess the combined effects on the response variable. The quantitation developed was used to calculate concentration of each indomethacin solid phase (amorphous, alpha and gamma) in all the samples. METHOD(S) Preparation of α-Indomethacin: A solvent-evaporation method was used to prepare the metastable form (α-form) of IMC. 30 grams of γ-IMC was dissolved in 450ml of ethanol at 50 ⁰C. The ethanol was then removed from the solution using a RotaVapor at a temperature of 50 ⁰C. The precipitated crystals were then collected and dried overnight in a desiccator under vacuum at room temperature. After drying, the crystals were screened through #30 sieve and collected. Preparation of amorphous Indomethacin: A quench cooling method was used to prepare amorphous IMC. 30 grams of γ-IMC was completely melt on a hot plate at 165 o C, then the melt was poured directly into the liquid nitrogen for immediate cooling. Collected products were gently grinded using agate motor and pestle. Characterization and Quantitation: DSC, powder X-ray Diffraction and In-situ Fiber Optic UV testing system were used to characterize the IMC before and after those processes. A XRPD quantitation method using full pattern fitting was developed in Microsoft Excel and was used to determine the solid state composition changes in the final granules as well as in-process samples. ACKNOWLEDGEMENTS We gratefully thank the Natoli Institute for Industrial Pharmacy Research and Development and Lachman Institute for Pharmaceutical Analysis, Long Island University for financial support. We gratefully thank Dr. Simon Bates for his help on developing the XRPD quantitation method for this study. Poster Number: T8011 INTRODUCTION Active Pharmaceutical Ingredients have to maintain their specific solid form, or transfer to their target solid forms during and after the manufacturing processes. The pharmaceutical industry employs various processes for granulation. Melt granulation is clearly distinguished from other techniques because of the level of mechanical stress, thermal stress and liquid exposure been induced during the process. By varying the batch processes, different stresses may be introduced and controlled and different transformation mechanisms will be enabled. This and the thermodynamics determine the possible polymorphic transitions during the processes. Blend preparation and HMG process: α- Indomethacin was blended with PEG3350 (4:1 w/w) using V-blender at 20 RPM for 20 mins. Approximately 15 gram of the blend was loaded into hot melt extruder (co-rotating twin-screw HME) for melt granulation. The HMG process and variables were detailed in the figure on the right side. • According to the DSC and PXRD data, 100% α-indomethacin and amorphous were obtained from solvent-evaporation and quench cooling method, respectively. The melting point of the indomethacin was 154.1 ⁰C for the α-form in contrast to 160.2 ⁰C for the γ-form. The glass transition temperature of the amorphous IMC was 43.65±1.80 o C. Powder X-ray diffraction patterns agreed with the calculated patterns obtained from CDCC structures of both forms. Intrinsic dissolution rates of the polymorphs were determined using the Wood’s apparatus with the in-situ fiber-optics UV system. Figures on the right-hand side show the intrinsic dissolution profiles for α and γ form indomethacin and XRPD patterns for α, γ form and amorphous IMC. • Results indicated that transitions through the heating stage during the melt granulation process changes from the meta-stable starting material to produce the g-form with an increase in the processing stresses from both heating and shearing. During the melt granulation process designed on the extruder, heating is the major parameter which determined the transition route and extent. Shear stresses generated from the co-rotating screws have an additional effects always increasing the extent of the transition. During cooling, an increase in the peak intensities for a-form or re-appearance of a-form in the final granules was proved to be resulted from the recrystallization of amorphous/dissolved indomethacin. The percentage of Alpha-IMC in the granules under various processing conditions have been detailed in the Parallel Coordinate plot on the right hand side. Processes which obtained a percentage of Alpha above 95% were considered acceptable and are marked in green.
Transcript of Poster Modeling the Process-Induced Phase … · Modeling the Process-Induced Phase Transformation...
Modeling the Process-Induced Phase Transformation of Indomethacin during the Melt Granulation process on Hot Melt ExtruderTing Xu1, Kenneth R. Morris2, Rutesh H. Dave3
1Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, NY, USA2Lachman Institute for Pharmaceutical Research, Long Island University, NY, USA3Natoli Institute for Industrial Pharmacy Research and Development, Long Island University, NY, USA
PURPOSEAs an emerging platform for granulation, the twin-screw extrusion has various advantages over other techniques as it’s a continuous and solvent-free process and has higher efficiency in mixing and temperature control. In our study, the possible solid form changes during the granulation processes of a metastable form Indomethacin (IMC) were monitored and controlled by evaluating the effect of various forms and intensities of stresses which are experienced by the drug. Possible transitions in response to these are identified and model based design spaces are developed in order to control the final dosage form performance.
CONCLUSION(S)• A continuous melt granulation method for an indomethacin-PEG 3350 formulation was developed on a Steer hot melt extruder. A
design space was established with varying processing parameters in order to understand and control the possible solid state transformations of the API during this process. The results show that under processing stresses the extent of transition as well as the transformation routes occurred and can be controlled. The relative contribution of shear stress and temperatures induced the amorphization/disordering and/or a polymorphic transformation was examined and showed temperature to be the most critical process parameter.
• Careful control of the processing parameters was required in order to achieve the desired granule properties and dissolution characteristics and the basis for developing a design space for production and scale-up.
RESULT(S)
• The XRPD quantitation method was built around normalized measured reference patterns for the indomethacin solid phases and PEG 3350. The scale factors for each of the normalized reference patterns were optimized using the Excel Solver (GRG nonlinear) function to minimize the difference between calculated and measured XRPD data. All measured and reference data used in the method were collected under the same conditions and were initially background subtracted to remove the instrumental contribution and subsequently normalized to give a constant integrated intensity. For each unknown data set, a model powder pattern was calculated by a linear combination of data from the reference patterns. The magnitude of each reference pattern in the linear combination was adjusted by a scale factor. To allow for sample displacement errors, a variable angular offset was included in the model calculation. By adjusting the individual scale factors and the angular offset, the Excel Solver (GRG nonlinear) function minimized the difference between the calculated model data and unknown data. The returned scale factors were used as quantitative measures of the concentration of each phase in the unknown material.
• A continuous process which can combine two sequential stages (melting and mixing, and cooling) was employed to manufacture granules in this study. The basis of a design space was developed by setting the input variables (temperature at each functioning zone and size/design of kneading blocks on each screw) and monitoring the resulting product to assess the combined effects on the response variable. The quantitation developed was used to calculate concentration of each indomethacin solid phase (amorphous, alpha and gamma) in all the samples.
METHOD(S)Preparation of α-Indomethacin: A solvent-evaporation method was used to prepare the metastable form (α-form) of IMC. 30 grams of γ-IMC was dissolved in 450ml of ethanol at 50 ⁰C. The ethanol was then removed from the solution using a RotaVapor at a temperature of 50 ⁰C. The precipitated crystals were then collected and dried overnight in a desiccator under vacuum at room temperature. After drying, the crystals were screened through #30 sieve and collected. Preparation of amorphous Indomethacin: A quench cooling method was used to prepare amorphous IMC. 30 grams of γ-IMC was completely melt on a hot plate at 165 oC, then the melt was poured directly into the liquid nitrogen for immediate cooling. Collected products were gently grinded using agate motor and pestle.
Characterization and Quantitation: DSC, powder X-ray Diffraction and In-situ Fiber Optic UV testing system were used to characterize the IMC before and after those processes. A XRPD quantitation method using full pattern fitting was developed in Microsoft Excel and was used to determine the solid state composition changes in the final granules as well as in-process samples.
ACKNOWLEDGEMENTSWe gratefully thank the Natoli Institute for Industrial Pharmacy Research and Development and Lachman Institute for Pharmaceutical Analysis, Long Island University for financial support.
We gratefully thank Dr. Simon Bates for his help on developing the XRPD quantitation method for this study.
Poster Number:
T8011
INTRODUCTIONActive Pharmaceutical Ingredients have to maintain their specific solid form, or transfer to their target solid forms during and after the manufacturing processes. The pharmaceutical industry employs various processes for granulation. Melt granulation is clearly distinguished from other techniques because of the level of mechanical stress, thermal stress and liquid exposure been induced during the process. By varying the batch processes, different stresses may be introduced and controlled and different transformation mechanisms will be enabled. This and the thermodynamics determine the possible polymorphic transitions during the processes.
Blend preparation and HMG process: α-Indomethacin was blended with PEG3350 (4:1 w/w) using V-blender at 20 RPM for 20 mins. Approximately 15 gram of the blend was loaded into hot melt extruder (co-rotating twin-screw HME) for melt granulation. The HMG process and variables were detailed in the figure on the right side.
• According to the DSC and PXRD data, 100% α-indomethacin and amorphous were obtained from solvent-evaporation and quench cooling method, respectively. The melting point of the indomethacin was 154.1 ⁰C for the α-form in contrast to 160.2 ⁰C for the γ-form. The glass transition temperature of the amorphous IMC was 43.65±1.80oC. Powder X-ray diffraction patterns agreed with the calculated patterns obtained from CDCC structures of both forms. Intrinsic dissolution rates of the polymorphs were determined using the Wood’s apparatus with the in-situ fiber-optics UV system. Figures on the right-hand side show the intrinsic dissolution profiles for α and γ form indomethacin and XRPD patterns for α, γ form and amorphous IMC.
• Results indicated that transitions through the heating stage during the melt granulation process changes from the meta-stable starting material to produce the g-form with an increase in the processing stresses from both heating and shearing. During the melt granulation process designed on the extruder, heating is the major parameter which determined the transition route and extent. Shear stresses generated from the co-rotating screws have an additional effects always increasing the extent of the transition. During cooling, an increase in the peak intensities for a-form or re-appearance of a-form in the final granules was proved to be resulted from the recrystallization of amorphous/dissolved indomethacin. The percentage of Alpha-IMC in the granules under various processing conditions have been detailed in the Parallel Coordinate plot on the right hand side. Processes which obtained a percentage of Alpha above 95% were considered acceptable and are marked in green.
