Author(s): Silambarasan I, Rajalakshmi AN


DOI: 10.52711/0974-360X.2022.00813   

Address: Silambarasan I1*, Rajalakshmi AN2
Department of Pharmaceutics, Mother Theresa Post Graduate and Research Institute of Health Sciences, Indira Nagar, Gorimedu, Puducherry - 605006, India.
*Corresponding Author

Published In:   Volume - 15,      Issue - 10,     Year - 2022

Freeze-drying is effective technique used in pharmaceutical industry to increase the efficacy, shelf-life of formulations and makes easier to transport and storage. Freeze-drying applies to the product that is thermolabile and unstable in solution form, because of utilization of low temperature and pressure. Nowadays freeze-drying gained so much attention in the development of parenteral formulation especially vaccines. The selection of excipients plays a key role in development of freeze-dried product and used to improve the shelf life and makes the product cost effective. The structure of cake not only focuses on appearance of product and also provide information about issues on drying stage that impact quality of product. Tray style freeze dryer helps in development of long-term storage vaccines and labile drugs. It performs freeze drying in containers or in vials on large quantities. This makes tray style freeze dryer become most common for developing lyophilized product. The need for improve the shelf-life of protein-based drug and antibiotics formulations makes tremendous growth of freeze-dried product market. This review focuses on the lyophilization process, design of freeze dryer, role of excipients in lyophilization process, decision of selecting the excipients, importance of cake structure helps to develop stable lyophilized drug product for long-term usage and applications of lyophilization technology.

Cite this article:
Silambarasan I, Rajalakshmi AN. A Review on Freeze-drying: A Stability Enhancement Technique. Research Journal of Pharmacy and Technology 2022; 15(10):4841-6. doi: 10.52711/0974-360X.2022.00813

Silambarasan I, Rajalakshmi AN. A Review on Freeze-drying: A Stability Enhancement Technique. Research Journal of Pharmacy and Technology 2022; 15(10):4841-6. doi: 10.52711/0974-360X.2022.00813   Available on:

1.    Deepak B, Iqbal Z. Lyophilization-Process and Optimization for Pharmaceuticals. International Journal of Drug Regulatory Affairs. 2015; 3(1): 30-40. doi:10.22270/ijdra.v3i1.156
2.    Akers MJ. Parenteral Preparations. Remington essentials of pharmaceutics, Edited by Linda Felton. Pharmaceutical Press, London. 2012; 1st ed: pp.525-32.
3.    Sandhya M, Disha K. Expension in the field of Freeze-drying: An advanced Review. Research Journal of Pharmacy and Technology. 2020; 13(5):2468-74. doi:10.5958/0974-360X.2020.00441.2 Available on: /AbstractView.aspx?PID=2020-13-5-71.
4.    Gangurde JS, Erande KB, Shevale LM. Freeze drying: A review. World Journal of Pharmaceutical Research. 2019 Feb 18; 8(3):592-603. doi:10.20959/wjpr20193-14335
5.    Kumar P. Lyophilization: An important formulation technique. International Journal of Research-Granthaalayah. 2019 Sep; 7(9):11-5. doi:10.5281/zeodo.3464308
6.    Gaidhani KA, Harwalkar M, Bhambere D, Nirgude PS. Lyophilization/freeze drying -A review. World Journal of Pharmaceutical Research. 2015 Jul 19; 4(8):516-43.
7.    Nireesha GR et al. Lyophilization/freeze-drying- An Review. International journal of novel trends in pharmaceutical sciences. 2013; 3(4):87-98.
8.    Anjali Pande, Pallavi Dhekale, Vikas Thorat. Lyophilization- A process of optimization of dosage form. Int J Pharm Sci Res. 2020; 11(10):4833-45. doi:10.13040/IJPSR.0975-8232.11(10).4833-45
9.    Khandagale PM, Bhairav B, Saudagar RB. Lyophilization Technique: A Review. Asian Journal of Research in Pharmaceutical Sciences. 2016; 6(4):269-76. doi:10.5958/2231-5659.2016.00038.2
10.    Williams NA, Lee Y, Polli GP, Jennings TA. The effects of cooling rate on solid phase transitions and associated vial breakage occurring in frozen mannitol solutions. J Parenter Sci Technol. 1986 Jul-Aug; 40(4):135-41.
11.    Adams GD, Irons LI. Some implications of structural collapse during freeze-drying using Erwinia caratovora L-asparaginase as a model. J Chem Technol Biotechnol. 1993; 58(1):71-6. doi:10.1002/jctb.280580110
12.    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 Jun; 72(6):635-50. doi:10.1002/jps.2600720614
13.    Searles JA, Carpenter JF, Randolph TW. Annealing to optimize the primary drying rate, reduce freezing-induced drying rate heterogeneity, and determine T(g)' in pharmaceutical lyophilization. J Pharm Sci. 2001 Jul; 90(7):872-87. doi:10.1002/jps.1040
14.    Tang X, Pikal MJ. Design of freeze- drying processes for pharmaceuticals: Practical advice. Pharm Res. 2004 Feb; 21(2):191-200. doi:10.1023/B:PHAM.0000016234.73023.75
15.    Pyne A, Chatterjee K, Suryanarayanan R. Solute crystallization in mannitol-glycine systems-implications on protein stabilization in freeze-dried formulations. J Pharm Sci. 2003 Nov; 92(11):2272-83. doi:10.1002/jps.10487
16.    Tang XC, Nail SL, Pikal MJ. Freeze-drying process design by manometric temperature measurement: design of a smart freeze-dryer. Pharm Res. 2005 Apr; 22(4):685-700. doi:10.1007/s11095-005-2501-2
17.    Wang DQ, Hey JM, Nail SL. Effect of collapse on the stability of freeze-dried recombinant factor VIII and alpha-amylase. J Pharm Sci. 2004 May; 93(5):1253-63. doi:10.1002/jps.20065
18.    Nail SL, Her LM, Proffitt CP, Nail LL. An improved microscope stage for direct observation of freezing and freeze drying. Pharm Res. 1994 Aug; 11(8):1098-100. doi:10.1023/a:1018972428858
19.    Wang W. Lyophilization and development of solid protein pharmaceuticals. Int J Pharm. 2000 Aug; 203(1-2):1-60. doi:10.1016/s0378-5173(00)00423-3
20.    Herman BD, Sinclair BD, Milton N, Nail SL. The effect of bulking agent on the solid-state stability of freeze-dried methylprednisolone sodium succinate. Pharm Res. 1994 Oct; 11(10):1467-73. doi:10.1023/a:1018908326074
21.    Korey DJ, Schwartz JB. Effects of excipients on the crystallization of pharmaceutical compounds during lyophilization. J Parenter Sci Technol. 1989 Mar-Apr; 43(2):80-3.
22.    Franks F. Freeze-drying of bioproducts: putting principles into practice. Eur J Pharm Biopharm. 1998 May; 45(3):221-9. doi:10.1016/s0939-6411(98)00004-6
23.    Mungikar A, Ludzinski M, Kamat M. Effect of the design of the stopper including dimension, type, and vent area on lyophilization process. PDA J Pharm Sci Technol. 2010 Nov-Dec; 64(6):507-16.
24.    Robertson MI. Regulatory issues with excipients. Int J Pharm. 1999 Oct; 187(2): 273-6. doi:10.1016/s0378-5173(99)00110-6
25.    Mehmood Y, Farooq U. Excipients use in parenteral and lyophilized formulation development. Open science journal of pharmacy and pharmacology. 2015; 3(3):19-27.
26.    Baheti A, Kumar L, Bansal AK. Excipients used in lyophilization of small molecules. Journal of Excipients and Food chemicals. 2016 Nov; 1(1):1135.
27.    Teagarden DL, Baker DS. Practical aspects of lyophilization using non-aqueous co-solvent systems. Eur J Pharm Sci. 2002 Mar; 15(2):115-33. doi:10.1016/s0928-0987(01)00221-4
28.    Israelachvili J, Wennerström H. Role of hydration and water structure in biological and colloidal interactions. Nature. 1996 Jan; 379(6562):219-25. doi:10.1038/379219a0
29.    Seager H, Taskis CB, Syrop M, Lee TJ. Structure of products prepared by freeze-drying solutions containing organic solvents. J Parenter Sci Technol. 1985 Jul-Aug; 39(4):161-79.
30.    Depaz RA, Pansare S, Patel SM. Freeze-Drying Above the Glass Transition Temperature in Amorphous Protein Formulations While Maintaining Product Quality and Improving Process Efficiency. J Pharm Sci. 2016 Jan; 105(1):40-9. doi:10.1002/jps.24705
31.    Awotwe-Otoo D, Agarabi C, Read EK, Lute S, Brorson KA, Khan MA, et al. Impact of controlled ice nucleation on process performance and quality attributes of a lyophilized monoclonal antibody. Int J Pharm. 2013 Jun; 450(1-2):70-8. doi:10.1016/j.ijpharm.2013.04.041
32.    Wittaya-Areekul S, Needham GF, Milton N, Roy ML, Nail SL. Freeze-drying of tert-butanol/water cosolvent systems: a case report on formation of a friable freeze-dried powder of tobramycin sulfate. J Pharm Sci. 2002 Apr; 91(4):1147-55. doi:10.1002/jps.10113
33.    Rambhatla S, Obert JP, Luthra S, Bhugra C, Pikal MJ. Cake shrinkage during freeze drying: a combined experimental and theoretical study. Pharm Dev Technol. 2005; 10(1):33-40. doi:10.1081/pdt-35871

Recomonded Articles:

Research Journal of Pharmacy and Technology (RJPT) is an international, peer-reviewed, multidisciplinary journal.... Read more >>>

RNI: CHHENG00387/33/1/2008-TC                     
DOI: 10.5958/0974-360X 

56th percentile
Powered by  Scopus

SCImago Journal & Country Rank

Recent Articles


Not Available