Use of Twin Screw Extruders as a Process Chemistry Tool: Application

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Use of Twin Screw Extruders as a Process Chemistry Tool: Application of Mechanochemistry to Support Early Development Programs Henry Grant Morrison, Peter Fung, To Tran, Elizabeth Horstman, Ernest Carra, and Steven Touba Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00253 • Publication Date (Web): 07 Sep 2018 Downloaded from http://pubs.acs.org on September 7, 2018

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Organic Process Research & Development

Use of Twin Screw Extruders as a Process Chemistry Tool: Application of Mechanochemistry to Support Early Development Programs Henry Morrison*, Peter Fung, To Tran, Elizabeth Horstman, Ernest Carra, and Steven Touba Gilead Sciences, Inc, 333 Lakeside Drive, Foster City, CA 94404, USA *To whom correspondence should be sent; [email protected]

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Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Abstract GS-X and GS-Y are novel active pharmaceutical ingredients selected for early clinical development. For each API, two slightly-hygroscopic unsolvated polymorphs were identified and investigations of these phases were required to identify the room temperature stable form. To support this, twin screw extruders were utilized to apply mechanochemistry for scale-up of GS-X and GS-Y polymorphs. Resulting materials were used to conduct solubility measurements to map relative stabilities so that crystallizations could be designed to ensure form control for the thermodynamically most stable form at room temperature.

Keywords: Twin Screw Extrusion, Polymorphism, Van’t Hoff plot, Form Selection, Polymorph Screening, Mechanochemistry Abbreviations: API = active pharmaceutical ingredient, TSE = twin screw extruders



Introduction Polymorphism occurs when two or more crystals have the same chemical composition but different internal structure (molecular packing)1, while polymorph screening and the formation of crystalline salts/co-crystals is an approach used for optimization of physical properties such as melting point, hygroscopicity, chemical stability, dissolution rate and crystal form.2-9 Once polymorphs of an API are identified, it is imperative to understand the phase transformation between the identified phases so that a process can be designed to isolated the thermodynamically most stable form at room temperature.10-12 GS-X (early stage) and GS-Y (Figure 1) are novel active pharmaceutical ingredients (API) selected for clinical development and via polymorph screening, two slightlyhygroscopic unsolvated phases were identified for each system (Figures 2 and 3). For GS-X, the differential scanning calorimetry (DSC) curve for Form A shows a small endothermic transition at 255 °C attributed to a solid to solid form conversion (verified by hot-stage microscopy) to Form B followed by an endothermic transition at 265 °C attributed to the melt of Form B, while the DSC curve for Form B shows a single endothermic transition at 264 °C attributed to its melt. Because the melt of Form A was not detected during the DSC run, the heat-of-fusion rule could not be applied to determine the relationship of the two polymorphs. For the thermodynamic stability of two polymorphs, the heat-of-fusion rule proposed by Burger and Ramberger states that if the higher melting form has the lower heat of fusion, the two forms are usually enantiotropic; otherwise they are monotropic.13 Enantiotropic systems are defined as systems where the relative stability of the two forms inverts at some transition temperature, while monotropic systems are defined as systems where a single form is always more stable regardless of the temperature.1 For GS-Y, the DSC curve for Form A shows a endothermic transition at 189 °C attributed to the melt of Form A followed by a small endothermic transition at 202 °C attributed to partial crystallization/conversion to and melt of Form B, while the DSC curve for Form B shows a single endothermic transition at 202 °C attributed to its melt. For this system, since Form B (the higher melting form) has a lower heat of fusion (68 J/g vs 111 J/g) compared to Form A (the lower melting form), the two forms appear to be related enantiotropically; whereby, Form B is the more stable form at higher temperature. To determine the relationship of the forms of GS-X and to confirm the relationship of the GS-Y forms and determine their transition temperature, solubility data as a function of temperature was required. Early small scale process batches of GS-X yielded either pure Form A or mixtures of Form A and B. Form B was initially characterized by heating Form A on the DSC to just past the first endothermic transition followed by characterization of the resulting solids. Similarly, early lots of GS-Y yielded Form A, and Form B was initially characterized by heat cycling Form A on the DSC through its melting temperature until the melting endotherm was no longer present followed by characterization of the resulting solids. In each case, a method was needed to isolate Form B for each system at gram scale so that solubility data could be collected. It has been recently demonstrated that liquid-assisted twin screw extrusion (TSE) is a viable process tool for making co-crystals and is an efficient, scalable, and environmentally


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friendly process.14,15 Therefore, it was the goal of this work to see if this machinery could also be utilized to apply mechanochemistry to generate gram scale of the polymorphs of GS-X and GS-Y to support process investigations of these APIs. Figure 1. GS-Y

Figure 2. Summary of XRPD patterns for GS-X forms A and B (top) and GS-Y forms A and B (bottom)



Figure 3. Summary of DSC curves for GS-X forms A and B (top) and GS-Y forms A and B (bottom)

Results and Discussion GS-X Form A vs B To determine the feasibility of using a TSE to generate Form B of GS-X via heated mechanochemistry, a benchtop unit (Figure 4) was utilized, whereby ~ 2 grams of Form A was passed through the TSE at 240 °C at 150 rotations per minute (rpm). Although the DSC data indicated that the transition occurs around 255 °C, a lower temperature was


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selected to see if the applied shear of the screw configuration could allow for conversion and avoid potential decomposition of the material. The resulting material was characterized via X-ray powder diffraction (XRPD) and found to have fully converted to Form B. This material was then used to run room temperature slurry experiments and small scale kinetic solubility measurements in simulated physiological fluids (SPF) to compare to Form A. Data from the SPF solubility experiments indicated that the two forms were similar; however, slurry interconversions of 1:1 mixtures of Form A and B after 2 weeks at room temperature in acetone and ethanol separately were shown to have fully converted to Form A. Although this indicated that Form A was the room temperature stable phase under these test conditions, it was still unknown if the two forms were monotropic or enantiotropic. Figure 4. Haake MiniLab II Micro Compounder with screw configuration (top, bench top scale) and Leistritz ZSE 18HP with screw configuration (bottom, industrial scale)



In order to generate large quantities of Form B (~20 grams) for collection of solubility data as a function of temperature, tests for physical/chemical stability, and experimentation of high temperature slurry interconversions, an industrial sized TSE (Figure 4) was utilized to see if it could repeat what was accomplished with the small scale bench top unit. As a use test, 5 grams of GS-X Form A was extruded utilizing a 100 °C loading zone followed by two consecutive 240 °C heating zones, a 150 °C cooling zone, and a room temperature powder deposition zone to mimic the bench top TSE test parameters. The industrial sized TSE had two co-rotating screws made up of fast to slow conveying elements that were rotated at 30 rpm. The resulting extruded powder was analyzed by XRPD and found to have fully converted to GS-X Form B (Figure 5); however, the material was visually seen to be discolored due to decomposition, which was not seen on the bench top TSE. In an effort to avoid decomposition, a second run was conducted where material was extruded at 235 °C and a screw rotation speed of 100 rpm. The resulting material was a white powder and XRPD analysis showed that the material had mostly converted to Form B with trace amounts of Form A (Figure 5). Based on these results, it was theorized that the process could be optimized to yield pure Form B by either passing the material through the TSE again for one more pass under current conditions, or to pass new material though the TSE at the same temperature but at a slower screw speed (~75 rpm). However, it was around this time that a new organic solvated form of GS-X was discovered (Form C), which was found to convert to Form B at a much lower temperature than Form A. Thus, focus was shifted on applying TSE on this new solvate as a means to make pure Form B on large scale. Figure 5. Characterization data of GS-X Form B from initial TSE runs compared to references.


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XRPD and thermal data for GS-X Form C are shown in Figure 6. Based on the TGA data, Form C completely desolvates by 150 °C, and XRPD analysis of a sample desolvated to 150 °C in the TGA indicated that it converted to Form B (90 degrees lower than the conversion temperature for Form A to B seen on the TSE). Because of this, ~20 g of Form C was extruded through the industrial TSE with a 100 °C loading zone followed by two consecutive 150 °C heating zones, a 100 °C cooling zone and finally a room temperature powder deposition zone. The TSE had two co-rotating screws made up of only fast conveying elements that were rotated at 30 rpm. Surprisingly, the XRPD analysis of the resulting material showed that Form C only partially converted to Form B (Figure 6). Upon reviewing the TGA analysis as function of time (Figure 7), the data shows that the desolvation process takes place over 5 to 6 minutes, whereas the migration time through the extruder was measured to be ~1 minute based on 30 rpm and screw configuration thereby explaining the partial conversion of the TSE material. Therefore, the material was extruded two more consecutive times with the same TSE screw configuration, but using 180 °C heating zones to increase the desolvation rate and a screw speed of 15 rpm to increase the migration time. The resulting material was analyzed by XRPD and determined to be pure Form B (Figure 6), and HPLC analysis indicated that the chemical purity of the TSE material was equivalent to the starting Form C material.



Figure 6. XRPD data of TSE runs using GS-X Form C as starting phase compared to references (top) and thermal data of GS-X Form C (bottom).


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Figure 7. GS-X Form C TGA analysis as a function of time 3.0

400

6.48min 12.27min

2.5

300

2.0

Temperature (°C)

Total Desolvation Time: 5 to 6 min.

Weight (mg)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


200

1.5

1.0

100

0

5

10

15

20 25 Time (min)

30

35

0 40

Solubility data was then collected for GS-X Forms A and B in 7:3 DMAc:water (v/v) as a function of temperature (Figure 8). The solubility data shows that over the temperature range investigated (~30-90 °C) Form A is less soluble (more stable) than Form B up to ~77 °C, and conversely Form B is less soluble (more stable) above ~77 °C, thus indicating an enantiotropic system. To confirm this transition temperature, slurry competition studies were conducted on 1:1 Form A:Form B mixtures in 7:3 DMAc:water (v/v) at temperatures from ~25 °C to 80 °C. The slurry competition study results after ~1 week of slurrying (Figure 9) indicated that Form A was more stable up to 60 °C and that Form B was more stable above 70 °C. The 65 °C temperature experiment indicated that a mixture of both phases were still present, suggesting that the transition temperature is close or equal to 65 °C. The difference between the high temperature slurry transition of ~65 °C versus the high temperature solubility measurement transition of 77 °C is attributed to the thermodynamics of the long term slurry experiments versus the kinetics of the solubility measurement (conducted at a ramp rate of 1 °C /min on a Crystal 16 multiple reactor station).



Figure 8. Summary of solubilities of GS-X form A and B in 7:3 DMAC:Water (v/v) as a function of temperature

Figure 9. XRPD results from slurry competition study of GS-X forms in 7:3 DMAC:Water (v/v) at various temperatures.


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Having acquired the solubility curves for both forms, the data was utilized to develop a crystallization to ensure form control of Form A by choosing a seeding temperature (60 °C) below the transition temperature of Forms A and B. 3.0 grams of Form A was placed in a vessel with 60 mL of 70:30 DMAc:water and heated with stirring (300 rpm) to 90 °C to yield a clear solution. This solution was then cooled to 60 °C over 15 minutes and seeded with 150 mg of Form A. The mixture was then held for 1 hour and cooled to 5 °C over 12 hours, after which 15 mL of water was added over 7 hours. Resulting solids were suction filtered, washed with 100 mL of water, and dried under nitrogen and found to be pure Form A via XRPD. An attempt to make pure Form B was conducted using the same crystallization described above, but rather, choosing a seeding temperature (70 °C) above the transition temperature of Forms A and B and seeding with pure Form B from the TSE process. Resulting solids were suction filtered, washed with 100 mL of water, and dried under nitrogen and found to be pure Form B via XRPD. GS-Y Form A vs B To determine if a TSE could be used to generate Form B of GS-Y via heated mechanochemistry, the industrial sized unit was utilized, whereby 50 grams of Form A was passed through the TSE using three different 193 °C heated zones at 30 rpm. A 170 °C zone was used as the powder loading zone and a room temperature zone was used for powder deposition. The material was visually seen to melt and convert back to a powder as it passed through the high temperature zones of the two co-rotating screws, which contained a mixture of conveying and kneading elements. The resulting material was characterized via XRPD and DSC and found to have fully converted to Form B (Figure 10), while HPLC analysis indicated that the chemical purity of the TSE material was equivalent to the starting Form A material.



Figure 10. Characterization data of GS-Y Form B from TSE run compared to reference


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Solubility data was then collected for GS-Y Forms A and B in 6:4 EtOH:water (v/v) as a function of temperature (Figure 11). The data shows that over the temperature range investigated (~30-75 °C) Form A is less soluble than Form B, indicating that Form A is the more stable form across this temperature range. In order to confirm the heat-offusion results from the DSC investigation, which suggested that the polymorphs were enantiotropic, the solubility data was plotted as the logarithm solubility versus inverse absolute temperature (1/T) for each phase (Van’t Hoff plot)16 and the data are shown in Figure 12. The exponential plots cross at 157 °C, which suggests that this is the transition temperature indicating that Form A is more stable below this point. The Van’t Hoff plot was plotted both linearly and exponentially (cross over temperature based on the linear plot was 162 °C), and the resulting curves were compared to the measured absolute solubility data to see the accuracy of the Van’t Hoff curves (Figure 12). The curves showed that when the data was plotted linearly, the resulting predicted solubility data was significantly lower for both forms, while when the data was plotted exponentially, the resulting predicted solubility data was in excellent agreement with the absolute solubility data. The Van’t Hoff plot is linear based on the assumption that the enthalpy and entropy are constant with temperature changes; however, in some cases they change dramatically with temperature and thus result in a polynomial or exponential fit.17-19 For this reason, the exponential curve was accepted to be the more accurate one for predicting the transition temperature via extrapolation. Figure 11. Summary of solubilities of GS-Y Form A and B in 6:4 EtOH:water (v/v) as a function of temperature

6:4 EtOH:Water Solubility 50

Form A

45

Solubility (mg/mL)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


40

Form B

35 30

Metastable Zone

25 20 15 10 y = 8.3187e0.0315x R² = 0.9636

5 0 0

10

20

y = 2.1088e0.0482x R² = 0.9846 30

40

y = 0.824e0.054x R² = 0.998 50

Temperature (°C)


60

70

80


Figure 12. GS-Y Van’t Hoff plot (top) and Van’t Hoff solubilities predicted by both linearly and exponentially plotted data vs measured absolute solubilities (below)


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Although the Van’t Hoff plot suggested a transition temperature of 157 °C (a temperature that would never be reached under process conditions), the metastable zone (Figure 10) indicated that seeding temperature point could be a critical attribute for controlling resulting form. Therefore the data was utilized to develop a crystallization to ensure form control of Form A by choosing a concentration and seeding temperature (68 °C) between the solubility curves of Forms A and B. 3.02 grams of Form A was placed in a vessel with 68 mL of 60:40 EtOH:water and heated with stirring (300 rpm) to 75 °C to yield a clear solution. This solution was then cooled to 68 °C over 15 minutes and seeded with 200 mg of Form A. The mixture was then held for 1 hour and cooled to 5 °C over 4 hours and stirred overnight. Resulting solids were suction filtered, washed with 100 mL of water, and dried under nitrogen and found to be pure Form A via XRPD. An attempt was made to isolate Form B whereby 1.5 grams of Form A was placed in a vessel with 34 mL of 60:40 EtOH:water and heated with stirring (300 rpm) to 75 °C to yield a clear solution. This solution was then cooled to 58 °C over 10 minutes and seeded with 100 mg of Form B from the TSE process. 58 °C was chosen as the seeding temperature because it lies between the solubility curve of Form B and the metastable zone curve (Figure 10). While at this elevated temperature, 75 mL of water was added over 30 minutes and then the mixture was hot filtered and resulting solids were washed with 20 mL of water and dried under nitrogen and found to be pure Form B via XRPD. Conclusions Twin screw extruders were successfully utilized to apply mechanochemistry for scale up of GS-X and GS-Y polymorphs so that solubility measurements could be conducted to map relative stabilities. For both systems, the polymorphs were found to be enantiotropically related and crystallizations were designed to ensure form control for the room temperature thermodynamic form. Experimental X-ray powder diffraction (XRPD) analysis was conducted on a diffractometer (PANalytical XPERT-PRO, PANalytical B. V., Almelo, Netherlands) using copper radiation (Cu Kα, λ = 1.541874). Samples were spread evenly on a zero background sample plate. The generator was operated at a voltage of 45 kV and amperage of 40 mA. Slits were Soller 0.02 rad, antiscatter 1.0°, and divergence. Scans were performed from 2 to 40° 2θ with a 0.0167 step size. Data analysis was performed using X’Pert Data Viewer V1.2d (PANalytical B.V., Almelo, Netherlands). X-ray powder diffraction analysis was also conducted on a diffractometer (Rigaku MiniFlex, Rigaku Corporation, Beijing, China) using copper radiation (Cu Kα, λ = 1.541874). Samples were spread evenly on a zero background sample plate. The generator was operated at a voltage of 40 kV and amperage of 15 mA. Scans were performed from 2 to 40° 2θ with a 0.050 degree step size and a speed of 2 degrees/minute. Data analysis was also performed using X’Pert Data Viewer V1.2d (PANalytical B.V., Almelo, Netherlands). Differential scanning calorimetry traces were produced by loading powder samples (1-5 mg) into open aluminum DSC pans and characterized on a TA Instruments Q 2000. Data



analysis was performed utilizing Universal Analysis 2000, TA Instruments. A heating rate of 10˚C/min was used to run as high at 300 °C. Thermogravimetric analysis (TGA) was used to evaluate sample weight loss as a function of temperature on either a Q5000 or Q500 (TA Instruments, New Castle, DE), by loading 1-10 mg of material onto a weighed pan and heating the sample to 350 °C at a rate of 10 °C/min. The sample and reference pans were under a 60 mL/min and 40 mL/min nitrogen purge, respectively. Data analysis was completed using Universal Analysis 2000 Version 4.5A (TA Instruments, New Castle, DE). Twin screw extrusion was performed with either a Haake MiniLab II Micro Compounder or a Leistritz ZSE 18HP utilizing 4-5 separate heating zones. The extruder temperature was controlled to a predetermined set point and varied for each system studied. Solubility measurements were conducted using a Crystal 16 multiple reactor station (Technobis Crystallization Systems). Vials were filled with API and 1 or 2 mL of solvent was added and samples stirred and heat cycled using a 1 °C/min heating ramp rate followed by 0.1 °C/min cooling ramp rate. Acknowledgements The authors thank Katrien Brak, Dominika Pcion and Morin Frick for API and HPLC support for GS-X, and Mark Scott and Quynh Iwata for API and HPLC support for GSY. Supporting Information Further experimental data. This material is available free of charge via the Internet at http://pubs.acs.org. References 1. Byrn, S.R.; Pfeiffer, R.R.; Stowell, J.S. Solid State Chemistry of Drugs, 2nd Edition, SSCI, Inc., West Lafayette, Indiana, 1999. 2. Gould, P. L. Salt Selection for Basic Drugs, Int. J. Pharm. 1986, 33, 201-217. 3. Bastin, R. J.; Bowker, M. J.; Slater, B. J. Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities, Org. Process. Res. Dev. 2000, 4, 427-435. 4. Stahl, P. H., Wermuth, C. G. Handbook of Pharmaceutical Salts: Properties, Selection and Use; Helvetica Chimica Acta, Zurich, 2002. 5. Gross, T. D.; Schaab, K.; Ouellette, M.; Zook, S.; Reddy, J. P.; Shurtleff, A.; Sacaan, A. I.; Alebic-Kolbah, T.; Bozigian, H. An Approach to Early-Phase Salt Selection: Application to NBI-75043, Org. Process. Res. Dev. 2007, 11 365-377. 6. Maurin, M. B.; Rowe, S. M.; Koval, C. A.; Hussain, M. A. Solubilization of Nicardipine Hydrochloride via Complexation and Salt Formation, J. Pharm. Sci. 1994, 83(10), 1418-1420.


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7. Kumar, L.; Amin, A.; Bansal, A. K. Salt Selection in Drug Development, Pharm. Technol. 2008, 3(32), 128-146. 8. Morrison, H.; Jona, J.; Walker, S. D.; Woo, J. C. S.; Li, L.; Fang. J. Development of a Suitable Salt Form for a GPR40 Receptor Agonist, Org. Process Res. Dev., 2011, 15 (1), 104–111. 9. Morrison, H.; Burke, B.; Lei, D.; Robertson, V.; Nagapudi, K.; Chan, J.; Gore, A.; Fang, J.; Jona, J. Development of a Suitable Physical Form for a Sphingosine-1phosphate Receptor Agonist, Org. Process Res. Dev. 2011, 15(6), 1336-1343. 10. Hu, Y.; Wikstrom, H; Byrn, S.R., Taylor, L.S. Estimation of the transition temperature for an enantiotropic polymorphic system from the transformation kinetics monitored using Raman spectroscopy, J Pharm Biomed Anal. 2007, 45, 546-551. 11. Morrison, H.; Quan, B.P.; Walker, S.D.; Hansen, K.B.; Nagapudi, K.; Cui, S. Appearance of a New Hydrated Form during Development: A Case Study in Process and Solid-State Optimization, Org. Process Res. Dev., 2015, 19 (12), 1842–1848. 12. Kiang, Y.H.; Bercot, E.A.; Wu, Q.; Liu, J.; Milburn, R.R.; Cohen, D.E., Borths, C.J.; Saw, R.E., Staples, R.J.; Davis, C.; Thiel, O.R. Selection of a Suitable Physical Form and Development of a Crystallization Process for a PDE10A Inhibitor Exhibiting Enantiotropic Polymorphism, Org. Process Res. Dev., 2015, 19 (12), 1849–1858. 13. Burger, A.; Ramberger, R. On the Polymorphism of Pharmaceuticals and Other Molecular Crystals. II. Applicability of Thermodynamic Rules, Mikrochim. Acta., 1979, 72, 273-316. 14. Daurio, D.; Medina, C.; Saw, R; Nagapudi, K.; Alvarez-Nunez, F. Application of Twin Screw Extrusion in the Manufacture of Cocrystals, Part I: Four Case Studies, Pharmaceutics 2011, 3, 582-600. 15. Morrison, H.; Mrozek-Morrison, M.; Toschi, J.; Luu, V.; Tan, H.; Daurio, D. High Throughput Bench-Top Co-crystal Screening via a Floating Foam Rack/Sonic Bath Method, Org. Process Res. Dev. 2013, 17(3), 533-539. 16. Higuchi, W.I.; Lau, P.K.; Higuchi, T.; Shell, J.W. Polymorphism and drug availability. Solubility relationships in the methylprednisolone system, J. Pharm. Sci. 1963, 52, 150-153. 17. Grant, D.J.W., Mehdizadeh, M., Chow, A.H.L, Fairbrother, J.E. Non-linear van't Hoff solubility-temperature plots and their pharmaceutical interpretation, Int. J. Pharm. 1984, 18, 25-38. 18. Naghibi, H., Tamura, A., Sturtevant, J.M. Significant discrepancies between van't Hoff and calorimetric enthalpies, Proc. Natl. Acad. Sci. 1995, 92, 5597-5599. 19. Galaon, T., David, V. Deviation from van't Hoff dependence in RP-LC induced by tautomeric interconversion observed for four compounds, J. Sep. Sci. 2011, 34(12), 1423-1428.


Use of Twin Screw Extruders as a Process Chemistry Tool: Application

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