LYOPHILIZATION - PROCESS AND OPTIMIZATION FOR PHARMACEUTICALS
Abstract
In this 21st century, Lyophilization emerges to be a novel trend for the drying of pharmaceuticals and biological that are thermolabile or are unstable in aqueous form but stable for longer periods in their dried form. This article provides an overview on the process of lyophilization, how the freeze drying cycle is designed, discussing several important parameters which are important for understanding of this process as well as their role in the designing of an optimized freeze drying cycle, so that a robust and economical process of lyophilization can be developed which does not impact the product quality. It also describes the use of this process in various industries.
Keywords:
Lyophilization, Stages of lyophilization, 1°drying, 2°drying, Excipients used for the process, applications.
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References
1. Pikal MJ. Freeze-drying of proteins. Part I: Process design. Bio Pharm. 1990; 3: 18-28.
2. Pikal MJ. Freeze-drying of proteins. Part II: Formulation selection. Bio Pharm. 1990; 3: 26-30.
3. Lippincolt. Remington WK. The Science & practice of pharmacy. Parenteral Preparation. 20th ed. Phelabelphia: ISE publication; 2000. P. 804-19.
4. Gatin LA, Auffret T, Shalaev EY, Speaker SM, Teagarden DL. Freeze Drying Concepts: The Basics, in McNally EJ and Hastedt JE (eds): Protein Formulation and Delivery. Informa Healthcare. New York: 2008. p. 177-95.
5. Nail SL, Gatin LA. Freeze drying: principles and practice, in Avis KE, Lieberman HA Lachman L (eds): Pharmaceutical Dosage Forms: Parenteral Medications. New York. NY: Marcel Dekker; 1993. p. 163-233.
6. Liberman HA, Lachman L, Schwartz BJ. Pharmacueutial dosage form: Parenterals. Vol. 1. Marcel Dekker publisher; 1989.
7. Yie CW. Pharmaceutical Dosage Forms: Parenteral medications. Ind J Pharm Sci Tech. 1981; 35:106-18.
8. Tang XC. Pikal MJ. Design of freeze-drying processes for pharmaceuticals: Practical advice. Pharmaceutical Research; 2004.p. 191-200.
9. Barbaree JM, Sanchez A. Cross contamination during lyophilization. Cryobiology; 1982. p. 443-47.
10. Barbaree JM, Sanchez A, Sanden GN. Problems in freeze-drying: II. Cross contamination during lyophilization. Developments in industrial microbiology; 1985. p. 407-9.
11. Hawe MJ, Fries P. The impact of the freezing stage in lyophilization: Effects of the ice nucleation temperature on process design and product quality. Am Pharm Rev; 2002.p. 48–53.
12. Antonsmith T, Pikal MJ, Rambhatla S, Ramot R. Formulation and evaluation of tigeyline injection by lyophilization. USA: Inter Pharm Press; 1997. p.242-49.
13. Tsinotides N, Baker DS. The importance of freezing on lyophilization cycle development. Asi J Biopharm. 2002; 19:16–21.
14. Barbaree JM. Smith SJ. Loss of vacuum in rubber stoppered vials stored in aliquid nitrogen vapor phase freezer. Cryobiology. 1981; 18: p.528-31.
15. Cammack KA, Adams GDJ. Formulation and storage animal cell biotechnology. Vol. II. Ed. Spier RE. Griffiths JB. London; Acamedic press; 1985..
16. Abdelwahed W, Thomas E, David E. The Importance of Freezing on Lyophilization Cycle Development. Biopharm; 2002.p. 16-21.
17. Drummond JN, Day LA. Influence of vial construction and material on performance and morphology during freezing and freeze drying. Osaka. Japan: PDA Internationnal congress; 1997.
18. Beals JM, Edwards MJ, Pikal MJ, Rinella JV. Formulation of obesity protein. USA: Eur Pat Appl (Eli Lilly and co. USA). EP; 1997.p. 48.
19. Carpenter JF, Pikal MJ, Chang BS.Randolph TW. Rational design of stable lyophilized protein formulations: some practical advice. Pharm Res. 1997;14: 969-75.
20. Adams GD, Irons LI. Some implications of structural collapse during freeze drying using Erwinia caratovora l-asparaginase as a model. J Chem Biotechnol. 1993; 58:71-6.
21. Murase N, Franks F. Salt precipitation during the freeze-concentration of phosphate buffer solutions. Biophys Chem. 1989;. 34: 293-300.
22. Shalaev E, Johnson T, Change L, Pikal MJ. Thermophysical properties of pharmaceutically comptabile buffers at sub-zero temperatures: implications for freeze drying. Pharm Res. 2002; 19:195-211.
23. Jiang S, Nail SL. Effect of process conditions on recovery of protein activity after freezing and freeze-drying. Eur J Pharm Biopharm. 1998; 45: 249–57.
24. Heller MC, Carpenter JF, Randolph TW. Protein formulation and lyophilization cycle design: prevention of damage due to freeze concentration induced phase separation. Biotechnol Bioeng. 1999; 63:166-74.
25. Williams NA, Lee Y, Polli GP, Jennings TA. The effects of cooling rate on solid phase transitions and associated vial brekage occuring in frozen mannitol solutions. J Parenter Sci Technol. 1986; 40:135-41.
26. Pyne A, Surana R, Suryanarayanan R. Crystallization of mannitol below Tg’ during freeze-drying in binary and ternary aqueous systems. Pharm Res. 2008; 19:901–8.
27. Pikal MJ, Shah S, Senior D, Lang JE. Physical chemistry of freeze-drying: measurement of sublimation rates for frozen aqueous solutions by a microbalance technique. J Pharm Sci. 1983; 72:635–50.
28. Searles JA, Carpenter JF, Randolph TW. Annealing to optimize the primary drying rate, reduce freezing induced drying rate heterogeneity and determine Tg’ in pharmaceutical lyophilization. J Pharm Sci. 1999; 90:872-87.
29. Pikal MJ, Roy ML, Shah S. Imporatnce of freeze dried pharmaceuticals: role of the vial. J Pharm Sci. 1984; 73(9): 1224-37.
30. Milton N, Pikal MJ, Roy ML, Nail SL. Evaluation of manometric temperature measurement as a method of monitoring product temperature during lyophilization. PDA J Pharm Sci Technol. 1997; 51:7–16.
31. Tang XC, Nail SL, Pikal MJ. Freeze drying process optimation by manometric temperature. Denver Colorado: AAPS Annual Meeting; 2001.
32. Tang XC, Nail SL, Pikal MJ. Mass transfer in freeze drying: measurement of dry layer resistance by a non-steady state method (the MTM procedure). New Orleans. Louisiana: AAPS Anual Meeting; 1999.
33. Charles P, Detke HC, Pyne A. Post injection delirium/sedation syndrome in patients with schizophrenia treated with Olanzapine long acting injection: analysis of cases. BMC psychiatry; 2005.
34. Pikal MJ, Shah S, Roy ML, Putman R. The secondary drying stage of freeze drying: drying kinetics as a function of temperature and chamber function. Int J Pharm. 1990; 60: 203-17.
35. Kamat MS, Lodder RA, Deluca PP. Near-infrared spectroscopic determination of residual moisture in lyophilized sucrose through intact glass vials. Pharm. Res. 1989; 6:961-65.
36. Jennings TA. Effect of formulation on lyophilization. Part 1. IVD Technology Magazine; 1997.
37. Sugimoto I, Ishihara T, Habata H, Nakagawa H. Stability of lyophilized sodium prasterone sulfate. J Parenter Sci Technol. 1981; 35:88-92.
38. Cappola ML: Freeze-Drying Concepts: The Basics, in McNally EJ (ed.): Protein Formulation and Delivery. New York. NY: Marcel Dekker; 2000. P. 159-99.
39. Korey DJ. Schwartz JB. Effects of Excipients on the crystallization of pharmaceutical compounds during lyophilization. Journal of parenteral science and technology. A publication of the Parenteral Drug Association. 1989. 43; 80-83.
40. Reich I. Schnaare R. Tonicity, osmoticity, osmolalality, osmolarity, in Remington (ed). The Science and Practice of Pharmacy. PA. Mack Publishing Co; 2000.p. 246-62.
41. Shalaev EY. The impact of buffer on processing and stability of freeze-dried dosage forms. Am Pharm Rev. Part 1. 2005; 8:80-7.
42. Shalaev EY, Wang W, Gatin LA. Rational choice of Excipients for use in lyophilized formulations. In McNally EJ and Hastedt JE (eds). Protein formulation and delivery. New York. NY: Informa Healthcare. 2008;175:197-217.
43. Inactive Ingredient Guide. Division of Drug Information Resources. FDA. Center for Drug Evaluation and Research [Internet]. FDA, Silver spring; 2013 Oct 13 [cited 2014 Dec 27]. Available from: http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm.
44. Pikal MJ. Freeze drying, in Swarbrick J. and Boylan JC (eds): Encyclopedia of Pharmaceutical Technology. New York . NY: Marcel Dekker Inc; 1992.p. 275-303.
45. Pikal MJ. Freeze-Drying of proteins: Process, Formulation and Delivery of Proteins and Peptides. Washington DC. American Chemical Society; 1994.
46. Wang W. Lyophilization and development of solid protein pharmaceuticals. Int J Pharm. 2000; 52:1-60.
47. Pikal MJ, Swarbrick J. Concept of freeze drying. Int J Pharm Sci. 2007;47:187-93.
2. Pikal MJ. Freeze-drying of proteins. Part II: Formulation selection. Bio Pharm. 1990; 3: 26-30.
3. Lippincolt. Remington WK. The Science & practice of pharmacy. Parenteral Preparation. 20th ed. Phelabelphia: ISE publication; 2000. P. 804-19.
4. Gatin LA, Auffret T, Shalaev EY, Speaker SM, Teagarden DL. Freeze Drying Concepts: The Basics, in McNally EJ and Hastedt JE (eds): Protein Formulation and Delivery. Informa Healthcare. New York: 2008. p. 177-95.
5. Nail SL, Gatin LA. Freeze drying: principles and practice, in Avis KE, Lieberman HA Lachman L (eds): Pharmaceutical Dosage Forms: Parenteral Medications. New York. NY: Marcel Dekker; 1993. p. 163-233.
6. Liberman HA, Lachman L, Schwartz BJ. Pharmacueutial dosage form: Parenterals. Vol. 1. Marcel Dekker publisher; 1989.
7. Yie CW. Pharmaceutical Dosage Forms: Parenteral medications. Ind J Pharm Sci Tech. 1981; 35:106-18.
8. Tang XC. Pikal MJ. Design of freeze-drying processes for pharmaceuticals: Practical advice. Pharmaceutical Research; 2004.p. 191-200.
9. Barbaree JM, Sanchez A. Cross contamination during lyophilization. Cryobiology; 1982. p. 443-47.
10. Barbaree JM, Sanchez A, Sanden GN. Problems in freeze-drying: II. Cross contamination during lyophilization. Developments in industrial microbiology; 1985. p. 407-9.
11. Hawe MJ, Fries P. The impact of the freezing stage in lyophilization: Effects of the ice nucleation temperature on process design and product quality. Am Pharm Rev; 2002.p. 48–53.
12. Antonsmith T, Pikal MJ, Rambhatla S, Ramot R. Formulation and evaluation of tigeyline injection by lyophilization. USA: Inter Pharm Press; 1997. p.242-49.
13. Tsinotides N, Baker DS. The importance of freezing on lyophilization cycle development. Asi J Biopharm. 2002; 19:16–21.
14. Barbaree JM. Smith SJ. Loss of vacuum in rubber stoppered vials stored in aliquid nitrogen vapor phase freezer. Cryobiology. 1981; 18: p.528-31.
15. Cammack KA, Adams GDJ. Formulation and storage animal cell biotechnology. Vol. II. Ed. Spier RE. Griffiths JB. London; Acamedic press; 1985..
16. Abdelwahed W, Thomas E, David E. The Importance of Freezing on Lyophilization Cycle Development. Biopharm; 2002.p. 16-21.
17. Drummond JN, Day LA. Influence of vial construction and material on performance and morphology during freezing and freeze drying. Osaka. Japan: PDA Internationnal congress; 1997.
18. Beals JM, Edwards MJ, Pikal MJ, Rinella JV. Formulation of obesity protein. USA: Eur Pat Appl (Eli Lilly and co. USA). EP; 1997.p. 48.
19. Carpenter JF, Pikal MJ, Chang BS.Randolph TW. Rational design of stable lyophilized protein formulations: some practical advice. Pharm Res. 1997;14: 969-75.
20. Adams GD, Irons LI. Some implications of structural collapse during freeze drying using Erwinia caratovora l-asparaginase as a model. J Chem Biotechnol. 1993; 58:71-6.
21. Murase N, Franks F. Salt precipitation during the freeze-concentration of phosphate buffer solutions. Biophys Chem. 1989;. 34: 293-300.
22. Shalaev E, Johnson T, Change L, Pikal MJ. Thermophysical properties of pharmaceutically comptabile buffers at sub-zero temperatures: implications for freeze drying. Pharm Res. 2002; 19:195-211.
23. Jiang S, Nail SL. Effect of process conditions on recovery of protein activity after freezing and freeze-drying. Eur J Pharm Biopharm. 1998; 45: 249–57.
24. Heller MC, Carpenter JF, Randolph TW. Protein formulation and lyophilization cycle design: prevention of damage due to freeze concentration induced phase separation. Biotechnol Bioeng. 1999; 63:166-74.
25. Williams NA, Lee Y, Polli GP, Jennings TA. The effects of cooling rate on solid phase transitions and associated vial brekage occuring in frozen mannitol solutions. J Parenter Sci Technol. 1986; 40:135-41.
26. Pyne A, Surana R, Suryanarayanan R. Crystallization of mannitol below Tg’ during freeze-drying in binary and ternary aqueous systems. Pharm Res. 2008; 19:901–8.
27. Pikal MJ, Shah S, Senior D, Lang JE. Physical chemistry of freeze-drying: measurement of sublimation rates for frozen aqueous solutions by a microbalance technique. J Pharm Sci. 1983; 72:635–50.
28. Searles JA, Carpenter JF, Randolph TW. Annealing to optimize the primary drying rate, reduce freezing induced drying rate heterogeneity and determine Tg’ in pharmaceutical lyophilization. J Pharm Sci. 1999; 90:872-87.
29. Pikal MJ, Roy ML, Shah S. Imporatnce of freeze dried pharmaceuticals: role of the vial. J Pharm Sci. 1984; 73(9): 1224-37.
30. Milton N, Pikal MJ, Roy ML, Nail SL. Evaluation of manometric temperature measurement as a method of monitoring product temperature during lyophilization. PDA J Pharm Sci Technol. 1997; 51:7–16.
31. Tang XC, Nail SL, Pikal MJ. Freeze drying process optimation by manometric temperature. Denver Colorado: AAPS Annual Meeting; 2001.
32. Tang XC, Nail SL, Pikal MJ. Mass transfer in freeze drying: measurement of dry layer resistance by a non-steady state method (the MTM procedure). New Orleans. Louisiana: AAPS Anual Meeting; 1999.
33. Charles P, Detke HC, Pyne A. Post injection delirium/sedation syndrome in patients with schizophrenia treated with Olanzapine long acting injection: analysis of cases. BMC psychiatry; 2005.
34. Pikal MJ, Shah S, Roy ML, Putman R. The secondary drying stage of freeze drying: drying kinetics as a function of temperature and chamber function. Int J Pharm. 1990; 60: 203-17.
35. Kamat MS, Lodder RA, Deluca PP. Near-infrared spectroscopic determination of residual moisture in lyophilized sucrose through intact glass vials. Pharm. Res. 1989; 6:961-65.
36. Jennings TA. Effect of formulation on lyophilization. Part 1. IVD Technology Magazine; 1997.
37. Sugimoto I, Ishihara T, Habata H, Nakagawa H. Stability of lyophilized sodium prasterone sulfate. J Parenter Sci Technol. 1981; 35:88-92.
38. Cappola ML: Freeze-Drying Concepts: The Basics, in McNally EJ (ed.): Protein Formulation and Delivery. New York. NY: Marcel Dekker; 2000. P. 159-99.
39. Korey DJ. Schwartz JB. Effects of Excipients on the crystallization of pharmaceutical compounds during lyophilization. Journal of parenteral science and technology. A publication of the Parenteral Drug Association. 1989. 43; 80-83.
40. Reich I. Schnaare R. Tonicity, osmoticity, osmolalality, osmolarity, in Remington (ed). The Science and Practice of Pharmacy. PA. Mack Publishing Co; 2000.p. 246-62.
41. Shalaev EY. The impact of buffer on processing and stability of freeze-dried dosage forms. Am Pharm Rev. Part 1. 2005; 8:80-7.
42. Shalaev EY, Wang W, Gatin LA. Rational choice of Excipients for use in lyophilized formulations. In McNally EJ and Hastedt JE (eds). Protein formulation and delivery. New York. NY: Informa Healthcare. 2008;175:197-217.
43. Inactive Ingredient Guide. Division of Drug Information Resources. FDA. Center for Drug Evaluation and Research [Internet]. FDA, Silver spring; 2013 Oct 13 [cited 2014 Dec 27]. Available from: http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm.
44. Pikal MJ. Freeze drying, in Swarbrick J. and Boylan JC (eds): Encyclopedia of Pharmaceutical Technology. New York . NY: Marcel Dekker Inc; 1992.p. 275-303.
45. Pikal MJ. Freeze-Drying of proteins: Process, Formulation and Delivery of Proteins and Peptides. Washington DC. American Chemical Society; 1994.
46. Wang W. Lyophilization and development of solid protein pharmaceuticals. Int J Pharm. 2000; 52:1-60.
47. Pikal MJ, Swarbrick J. Concept of freeze drying. Int J Pharm Sci. 2007;47:187-93.
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How to Cite
Bisht, D., and Z. Iqbal. “LYOPHILIZATION - PROCESS AND OPTIMIZATION FOR PHARMACEUTICALS”. International Journal of Drug Regulatory Affairs, Vol. 3, no. 1, Feb. 2018, pp. 30-40, doi:10.22270/ijdra.v3i1.156.
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