Expension in the field of Freeze-drying: An Advanced Review

 

Mishra Sandhya*, Kesharwani Disha

Department of Pharmaceutics, Columbia Institute of Pharmacy, Near Vidhan Sabha, Raipur,

Chhattisgarh - 493111

 

ABSTRACT:

 

 

INTRODUCTION:

The term lyophilization or freeze-drying is defined as the process which involves sublimation of water from the product after freezing it.¹ The initial step involved in lyophilisation or freeze-drying is sublimation known as primary drying and then desorption known as secondary drying which results in the generation of a product that “loves the dry state” . This process is achieved by drying the frozen product under vacuum without allowing it to thaw out. In many cases, the term lyophilization and freeze-drying are used synonymously but freeze-drying is more expressive term.²

 

Freeze-drying as a practical commercial process was introduced around the time of the Second World War and found its first application in the preservation of blood plasma. Soon after world war second, the pharmaceutical industry began considering the process for the preparation of the sterile injectable dosage forms, which could not be formulated into stable solutions.^3-4

 

Freeze-drying is found to be very advantageous for the preparations which require low moisture content(less than 1%), are thermolabile and have low aqueous solution stability. Being an effective technique, the freeze-drying process has a minimum effect on the internal structure of the substance and hence does not affect its efficacy and quality. Freeze drying process found its application for manufacturing of parenteral preparations which are unstable in aqueous solution and are prone to microbial contamination. It has pharmaceutical applications and food industries. Other applications include the stabilization of living materials such as microbial cultures, preservation of whole animal specimens for museum display, restoration of books and other items damaged by water, and the concentration and recovery of reaction products.^5-6

 

Sublimation is the phenomenon on which the lyophilization principle is based. During the lyophilization process, water directly moves from solid (ice) to vapour state without passing through the liquid state. This process can be expressed by phase diagram of water as shown in figure.1 It occurs at pressure and temperature below triple point i.e. 4.579 mm of Hg and 0.0099 degree Celsius.⁷

 

Fig. 1 Phase Diagram of water

 

ADVANTAGES:

1. High Stability:

After freeze-drying the product obtained has certain characteristics which contribute to its high stability like

·       The process removes 95%-99.5% water content from the product and hence can be preserved for long time.

·       This process is favourable for the oxidizable products as it is placed under vacuum.

·       The whole process is carried out under an aseptic condition so chances of microbial contamination are very low.

·       The low temperature in the process also contributes to the high stability of the product as there is no effect of microbes and enzyme at low temperatures.

·       Sterility can be easily maintained.

·       The lyophilized preparations are chemically stable.⁸

 

2.   After the product is lyophilized:

·       It can be stored and transported at a normal temperature.

·       Constituents of the dried material remains homogenously dispersed.

·       It does not cause shrinkage or the toughening of the material being dried.

 

3.   Accuracy and Content uniformity:

·       The content of the dried material remains unchanged.

·       Flavors and smells also remain unchanged.

·       The process has an accurate loading quantity.

 

4.   Reconstitution:

·       The ice crystals when sublimated during the freeze-drying process, leaves microscopic pores and hence make the reconstitution easy.

·       Freeze dried products can be easily and quickly rehydrated (reconstituted).

·       After reconstitution, the product obtained has all the properties of original dosage form including solution properties; structure or conformation of proteins; and particle-size distribution of suspensions.

·       When preparation for parenteral use is reconstituted, it is found to be isotonic.⁴

 

DISADVANTAGES:

1. Time consuming:

·       It takes long time for the lyophilization of products which have a large quantity.

·       Lyophilisation of many pharmaceutical preparations needs a longer time making it a time consuming process.

 

2. Expensive:

·       A few parts of freeze dryer are costly and hence make the equipment expensive.

·       The price of freeze-drying treated products is steadily rising.⁹

 

3. The Freeze drying process is not favourable for all preparations

·       When proteins are exposed to freeze-drying then its denaturation takes place.

·       The bilayer of liposomes and emulsion structure can be disrupted by freeze stresses.

·       In the presence of high vacuum, the eviction of volatile compounds takes place.

·       The fragile substances like new antibiotics and drugs, immunological products, substances derived from genetic engineering and sophisticated peptides cannot freeze easily and have high sensitivity to residual moisture.

·       Melt back or collapse of amorphous materials take place during primary and secondary drying if not maintained below the critical point as they do not have eutectic point.¹⁰    

 

Two stages are involved in freeze drying:

1. Sublimation drying- Sublimation drying is the first stage that  involves the direct conversion of frozen water(ice crystals) into vapors, a process known as sublimation. A major part of the water content from the product being lyophilised is removed in this stage.

 

2. Desorption drying- This is the second stage which involves removal of unfrozen water adsorbed on the solid matrix.¹¹

 

STEPS REQUIRED TO LYOPHILISE A PRODUCT:

The steps required to lyophilize a product in a batch process as shown in figure 2 can be summarized as follows:

 

 

1. Formulation:

Firstly the sample is prepared using various agents listed below depending upon the type of formulation, route of administration and many other factors:

(a)  Buffers: Buffers are used to maintain the pH of the solution. E.g. Phosphate buffers, especially sodium phosphate, Tris, citrate, and histidine buffers.

(b)  Bulking Agents: When the concentration of API (active pharmaceutical ingredient) is low, then bulk enhancement of the formulation is required with the help of bulking agents.  Crystalline bulking agents are commonly used for small-chemical drugs and some peptides and have elegant cake strength and good mechanical properties however they are inappropriate for stabilizing products like emulsion, proteins and liposomes.

(c)  Stabilizers: Disaccharides such as sucrose and trehalose are commonly used for efficiently stabilizing products such as liposomes and proteins. They are inert in nature.

(d)  Tonicity Adjusters: The stability requirements of the bulk solution or those for the route of administration are the decisive factors for either using tonicity adjuster or not. Depending upon the route of administration and type of formulation, the tonicity adjuster is added. E.g. mannitol, sucrose, glycine, glycerol, and sodium chloride.¹²

 

2. Loading/Container (Bulk, Flask, Vials):

After the formulation is prepared, it is transferred to vials and for easy escape of water vapour a special slotted rubber closure is inserted halfway into the vial. Vials are placed on trays and transferred to freeze dryer. Trays of product are placed on shelves containing internal channels.¹³

 

3. Freezing (Thermal Treatment) at atmospheric pressure:

In the whole freeze-drying process, the freezing step is the most complex step, if not done properly it can badly affect the preparation. In this step the material is cooled below its eutectic point, the lowest temperature at which the solid and liquid phases of the material can coexist which ensures sublimation rather than melting in the further steps.

(a)  On laboratory scale, freeze-drying flask is used which is then equipped with shell freezer. The freeze-drying flask is rotated in shell freezer and is cooled by mechanical refrigeration, dry ice, and methanol, or liquid nitrogen. 

(b)  On large scale, a freeze drying machine is used for freezing.

 

Production of large crystals is favourable for the freeze drying process which is achieved by a process called annealing in which the product is frozen slowly and the temperature is cycled up and down. Usually, the freezing temperatures are between −50°C and −80°C. However this process is not advantageous for food items or objects with formerly living cells as large ice crystals will break the cell wall.^14-15  

 

4. Primary Drying (Sublimation) under vacuum:

This is the process in which sublimation of  water molecule (previously frozen) through the application of heat takes place. This process occurs under reduced pressure which is controlled by applying a partial vacuum. The utilisation of excess heat is avoided due to its effect on material’s structure and hence is a time taking process. The latent heat of sublimation of the sublimating molecule gives the estimate of amount of heat necessary.  In this phase, about 95% of water is sublimated.^16-17

 

5. Secondary Drying (Desorption) under vacuum:

Secondary drying aims at removal of unfrozen water which is not previously sublimated in the primary drying process. This process involves elevation of the temperature above primary drying temperature which can be above 0°C. The temperature to be assigned depends on the material’s adsorption isotherms. An increase in temperature can lead to the termination of physicochemical interaction between water molecules and frozen molecules. The pressure is also lowered in this stage to encourage desorption.¹⁸

 

6. Backfill and Stoppering (for product in vials) under partial vacuum:

After the product is freeze dried, closuring the product under vacuum is done to protect the product from deterioration by moisture and oxygen however it is not favourable for some products as like the products which are recovered by syringe or the substances which when opened are attacked by contaminated air. In these instances, the backfilling of the product container with inert gases in ultrapure form with no contamination like argon or nitrogen is done.

 

7. Removal of Dried Product from Freeze Dryer: When the process completes, the freeze dried product is unloaded .¹⁹

 

Fig. 2 Steps involved in lyophilisation from sample preparation to final product formation

 

EVALUATION PARAMETERS:

1.     Appearance For freeze dried products cake appearance is of great importance however it is not necessary that an ideal cake can be obtained in all cases depending on the formulation, drug product presentation and freeze-drying process. Patel et al provided a harmonized nomenclature and description for variations in cake appearance from the ideal expectation of uniform and elegant including representative images.²⁰

 

2.     Reconstitution time and clarity of reconstituted solution- The prepared lyophilised product should have minimum reconstitution time when reconstituted with the respected solvent and the reconstituted solution should be free from any solid particles.²¹

 

3.     Water content –There are certain methods for determination of residual water content in a lyophilised product and are listed below :

(a) Coulometric Karl Fischer Titration Method:

Coulometric karl fisher method is the most widely used method for determination of residual water content in  a lyophilised sample however this method is not favourable for some compounds such as aldehyde, ketones and thiols. However formulations having longer titration time (>4 min) for e.g. sera and blood with high protein content which cannot be easily suspend/dissolve needs frequent and regular change in cell solution and hence this method is disadvantageous for such substances.²² 

(b) Thermogravimetric analysis (TGA):

Thermogravimetric analysis is based on the principle of determination of weight loss when the heat is supplied to remove the residual moisture of the lyophilised product. Thermogravimetric analysis is more advantageous than the Karl Fischer titration method as it gives higher moisture detection and there is no chance of chemical contamination (for e.g. Iodine-binding components) .To measure error-free residual water content it is important to determine the composition of lyophilized product as the process measures volatiles which can be evolved by heating along with the water content. The method is however not favorable for substances which are sensitive to heat as like biological materials which may decompose at modest temperatures, for instance 100-150ºC. To overcome this problem, evolved water is driven off the sample and into an evolved gas analyzer (low molecular weight range quadrapole mass spectrometer) using a stream of dry inert gas such as helium).²³

 

(c) Near Infra Red Moisture Measurement:

This method has been used for moisture determination in both small molecules and biological products. Several authors have shown that the moisture detected correlated well with traditional coulometric Karl Fischer analysis. The method requires a standard curve to be generated using an identical lyophilized formulation and container diameter but which is acquiescent to Karl Fischer analysis.^24-25

 

4.     Assay: Determination of assay of a lyophilised product is very important for confirming whether the formulation after lyophilisation is pure and efficient enough to be used further. Assay can be done either by chromatographic techniques or microbial bioassay. A reference standard or a working standard with precise percent purity is used to compare the percent purity of lyophilised sample of unknown purity. Bio-assay is the process of determining potency of a substance against certain microorganism based on its ability to inhibit microbial growth in comparison with a reference standard. The assay is either reported as “Assay on the dried basis ” or “Assay as is .” Assay on “on dried basis” or “anhydrous” are calculated without water content. Assay on “as is” are calculated with water content.²⁶

 

5.     Stability: Stability testing is a very important aspect as it’s important to know how long the product can remain in a stable form without any chemical and physical change. This object can be fulfilled by placing the lyophilized product in stability chamber for long term stability studies and accelerated stability studies as per ICH guidelines.

 

6.     Sterility: To ensure sterility of a lyophilised product sterility test is performed after reconstituting it with water for injection or sterile water.²⁷

 

Table I :Pharmaceutical applications of lyophilization technique

	Application	Examples
1.	Bioproducts28	·       Freeze-drying method has its application in storing intact RNA in the freeze-dried tissues with no degradation as well as helps in interpreting the pathogenesis of CaP(carcinoma of the prostate) by isolating the intact RNA from prostate tissues.29 ·       Some authors claim they can freeze-dry erythrocytes, most critics are not convinced of those successes.28 ·       Freeze-drying is perpetually used to improve storage stability of therapeutic proteins. However it is important to protect the protein from freeze-drying-induced stresses which are fulfilled by using solutes specially trehalose and sucrose forming a glass layer and making a hydrogen bond with protein during lyophilization.30 ·       Freeze-drying is also commonly used for culture conservation and the production of concentrated starter cultures.28
2.	Food Industry	·         Freeze-drying process makes food products lightweight and hence transportation is easy and convenient.31 ·         A product with marvellous quality is obtained as the non-availability of liquid water and low temperature requirement helps in cessation of deterioration and microbiological reactions32 ·         The freeze-dried food items can be preserved for a long time without any change in physical and chemical characteristics.  ·         It is also a huge advantage for astronauts, hikers, and campers; they don't have to carry excess loads or worry about food spoiling. ·            It has also helped to preserve certain seasonal fruits, and make them available all year around.33
3.	Pharmaceuticals	·        With the application of freeze-drying, a sterile and freeze-dried nanoparticle of required size can be prepared.34    ·        The freeze-drying process finds its application in the  preparation of liposomes exhibiting high encapsulation capacity and efficient drug entrapment.35 ·        The freeze-drying process is used for the preparation of lyophilized dry emulsion powder for the delivery of  poorly soluble drugs.36 ·        Freeze-drying process helps in preparation of stable, sterile easy to transport lyophilised parenteral preparations with easy reconstitution.37 ·        Freeze-drying process finds its application in the preparation of a lyophilised anti-sclerostin antibody formulation which consists of one or more of a sugar , a buffering agent, a surfactant, and/or a free amino acid and can be effectively used for patients having low levels of antibody.38
4.	Others	·        On the basis of studies done by organizations such as the Document Conservation Laboratory at the United States National Archives and Records Administration (NARA) it  is observed that freeze-drying can be a recovery method of water-damaged books and documents. ·        Freeze-drying is also used for floral preservation and wedding bouquet preservation has become very popular with brides who want to preserve their wedding day flowers.39

 

Advance Applications of Freeze Drying Technique:

1.     For Drying Plant Extract- Spray drying was the conventional method for drying plant extract  showing many disadvantages of poor and inadequate drying leading to its damage which can be overcome by newly designed  vacuum freeze-drying device that consist of a material case, axis of rotation, vacuum pump, sterilamp and a voltage.⁴⁰

2.     For preparation of fast dissolving ketoprofen tablet- With the help of freeze-drying technique, lyophilised tablet of poorly water-soluble ketoprofen in blister packing is prepared which is found to be three folds more soluble than the plain drug.⁴¹

3.     For preparation of pH sensitive hydrogel with controlled delivery of antibiotics- A freeze-dried hydrogel is prepared by crosslinking chitosan and PVP blend with glutaraldehyde to form a semi-interpenetrating polymer network and an antibiotic is incorporated in it and showed superior drug-release properties in comparison to an air-dried hydrogel.⁴²

4.     For manufacturing of probiotic chewable tablet- A new freeze drying model is designed for the preparation lactic acid bacteria freeze drying powder centrifuge. This freeze-dried powder is used for the preparation of probiotic chewable tablet. The new model consists of a bottom plate, drying bottle, feed hopper, centrifuging chamber and cabinet.⁴³

5.     Advanced process unit for preparation of loratidine freeze-drying tablet- The conventional model is found to have fewer unit operations efficiency which is overcome by making an advanced process unit with efficient production of loratidine freeze-drying tablet.⁴⁴

6.     Preparation of freeze-dried rice- The preparation of freeze-dried rice is advantageous as it enhances the storage stability, easy to transport, can be recovered easily and also the nutrients are maintained. It’s reconstitution and cooking is easy.⁴⁵

7.      Preparation of granulated particles containing lyophilized strawberries-The prepared granulated particles contains a maximum degree of nutrient retention capacity and no disruption of colour, smell and taste.⁴⁶

 

Instrumental and Technical Advancements in Freeze Drying

1.     A modified instrument was designed by Zhaojian et al in 2019 which shows advanced characteristics improving the process. The characteristics include air-treatment unit, air conditioner cold water pipeline, refrigeration system and energy-saving fresh freeze drying system of low dew-point air supply. The designed model showed reduced investment, low operation energy consumption and economical expense of the fresh air dehumidifying system of low dew-point air supply.⁴⁷

2.     Chuansheng et al manufactured a new model of freeze drying in 2018.The conventional model of freeze drying is found to be unfavourable for medicinal plant materials as uneven drying of material takes place and can also lead to its damage and non-efficiency to recycle. The newly designed model consists of a cabinet with a layer of thermal insulation layer outside it with two refrigerators and an accumulating tank. This model guarantees uniform drying with good efficacy for medicinal plant material.⁴⁸

3.     The newly assembled model by Wei et al in 2018 is manufactured to solve the technical problem of slow pulsating charging rate of conventional freeze-drying apparatus which leads to slow freeze drying efficiency. The problem is solved by designing a kind of bigger surface continuous discharge freeze-drying apparatus with good efficacy.⁴⁹

4.     The newly designed system by Xianglin et al in 2018 is assembled with an automatic feeder to feed the sample in lyophilizer which has certain advantages in comparison to the previously designed freeze dryer with manual or half automated feeding of the product to be lyophilised. This model has the least chances of cross contamination, high precision and enhanced production efficacy.⁵⁰

5.     Xiobo et al in 2018 designed a model with less requirement of energy for operation of a freeze dryer. A low energy consuming freeze dryer is designed as the conventional model utilises significantly high power consumption. This model consists of an outer housing, dry storehouse, compressor and vacuum pump.⁵¹

6.     A new freeze dryer with a freeze drying box is manufactured by Maobin et al in 2017 and is more reliable and easy to adjust than the traditional freeze dryer system. The new model consists of a freeze drying box, freeze drying sheet layer, guide bar, go up extension board and lifting drive.⁵²

7.     A new model is designed by Kuan et al in 2017 having cooling system in the freeze- drying box body which is energy saving and the temperature is controllable.⁵³

 

CONCLUSION:

There is a massive advancement in lyophilization technique as there is an astonishing growth in its use in recent years. This process involves certain steps to be followed to lyophilize a product and is based on the simple principle of sublimation. From various advancements, technical as well as instrumental discussed in this review it can be concluded that this process is a very important tool and many products mandates the use of freeze-drying technique for achieving stability. The process of freeze-drying has its application in pharmaceuticals as well as in food industries, bioproducts and paper industry.

 

ACKNOWLEDGEMENT:

The author wish to thank and acknowledge the support provided by Columbia Institute of Pharmacy, Raipur, CG for providing all the necessary tools and sources for writing the review.

 

ABBREVIATIONS USED:

API: Active Pharmaceutical Ingredient; TGA: Thermogravimetric Analysis; ICH: International Council for Harmonisation; RNA: Ribonucleic acid; NARA: National Archives and Records Administration; PVP: Polyvinylpyrrolidone.

 

REFERENCE:

1.      Liu Y., Zhao Y., Feng X., Exergy analysis for a freeze-drying process, Appl Thermal Eng, 2008, 28, 675–690.

2.      Khairnar S, Kini R, Harwalkar M, Chaudhari SR., A Review on Freeze Drying Process of Pharmaceuticals, International Journal of Research in Pharmacy and Science, 2014 Jan 1;4(1).

3.      Louis Rey PhD et al.,” Sage of freeze drying” CH-1010. 5-8.

4.      Shukla S. Freeze Drying Process: a Review, International Journal of Pharmaceutical Sciences and Research, 2011 Dec 1; 2(12):3061-8.

5.      Nail SL. et al. Fundamentals of freeze-drying, Development and Manufacture of Protein Pharmaceuticals. Marcel Dekker, 2002; 281–360.

6.      Nireesha GR, Divya L, Sowmya C, Venkateshan NN, Babu MN, Lavakumar V. Lyophilization/freeze drying-an review. International Journal of Novel Trends in Pharmaceutical Sciences, 2013 Oct 4; 3(4):87-98.

7.      Chien and Yiew W. Pharmaceutical Dosageforms: Parenteral Medications. Indian Journal of Pharmaceutical Science and Technology, 1981, 35, 106-118.   

8.      Khandagale P.M., Bhairav B., Saudagar R.B., Lyophilization Technique: A Review, Asian Journal of Research in Pharmaceutical Science. 2016 6(4) 269-76.

9.      Shivanand A., Mukhopadhayaya S., A Review on Lyophilization: A Technique to Improve Stability of Hygroscopic, Thermolabile Substances. PharmaTutor,2017,  5(11) 28-39.

10.   Gaidhani K.A., Harwalkar M., Bhambere D., Nirgude P.S., Lyophilization/ freeze drying–a review. World Journal of Pharmaceutical Research, 2015, 4(8) 516-543.

11.   Tang X.C., Pikal M.J., Design of freeze-drying processes for pharmaceuticals: practical advice. Pharmaceutical Research. 2004, 21(2) 191-200.

12.   Shah R., Mehta P., Freeze dried injectable drug product development selection of non-functional additives, 2014, International Journal of Pharmacy and Pharmaceutical Sciences, 6(9)3-7.    

13.    Schwegman J.J., Hardwick L.M., Akers M.J., Practical formulation and process development of freeze-dried products, Pharmaceutical Development and Technology, 2005, 10(2)151-73.

14.   Franks F., Freeze-drying of bioproducts: putting principles into practice, European Journal of Pharmaceutics and Biopharmaceutics. 1998, 45 (3) 221–229.

15.   J. Li, T. Viverette, M. Virgin, M. Anderson, and P. Dalal, A study of the impact of freezing on the lyophilization of a concentrated formulation with a high fill-depth, Pharmaceutical Development and Technology. 2005, 10(2), 261– 272.

16.   Goldman J. M., More H. T., Yee O.,Optimization of primary drying in lyophilization during early-phase drug development using a definitive screening design with formulation and process factors, Journal of Pharmaceutical Sciences. 2018, 107(10), 2592–2600.

17.   Pikal M. J., Use of laboratory data in freeze drying process design: heat and mass transfer coefficients and the computer simulation of freeze drying, Journal of Parenteral Science and Technology. 1985, 39 115–139.

18.   Kawasaki H, Shimanouchi T, Kimura Y. Recent Development of Optimization of Lyophilization Process, Journal of Chemistry. 2019.

19.   https://www.spscientific.com/freeze-drying-lyophilization-basics/

20.   Patel S.M., Nail S.L., Pikal M.J., Geidobler R., Winter G., Hawe A., Davagnino J. and Gupta S.R., Lyophilized drug product cake appearance: what is acceptable? Journal of Pharmaceutical Sciences. 2017, 106(7) 1706-1721.

21.   Mikkilineni R., Srinivasa P.B., Mandava V.B., Formulation and evaluation of stable lyophilized bendamustine hydrochloride injection, Int. J. Pharm. Sci. Rev. Res., 2013, 23(2) 89-93.

22.   May J.C., Wheeler R.M., Elz N., Del G., A Measurement of final container residual moisture in freeze dried biological products, Dev. Biol. Standard., 1992, 74:153–164.

23.   May J.C., Grim E., Wheeler R.M., West J., Determination of residual moisture in freeze dried viral vaccines: Karl Fischer, gravimetric and thermogravimetric methodologies. Journal of Biological Standerdization. 1982, 10 249-59.

24.   Kamat M.S., Lodder R.A., DeLuca P.P., Near infra red spectroscopic determination of residual moisture in lyophilized sucrose through intact glass vials. Pharmaceutical  Research. 1989, 6(11) 961–965.

25.   Savage M., Torres J., Franks L., Determination of adequate moisture content for efficient dry-heat viral inactivation in lyophilised factor VIII by loss on drying and by near infra red spectroscopy. Biologicals.1998,26(2) 119–124

26.   do Vale Morais A.R., do Nascimento Alencar É., Júnior FH, De Oliveira CM, Marcelino HR, Barratt G, Fessi H, Do Egito ES, Elaissari A. Freeze-drying of emulsified systems: A review, International Journal of Pharmaceutics. 2016 Apr 30; 503(1-2):102-14.

27.   Mohammed A.R., Bramwell V.W., Coombes A.G., Perrie Y., Lyophilisation and sterilisation of liposomal vaccines to produce stable and sterile products. Methods. 2006, 40(1)30-38.

28.   Franks F., Freeze-drying of bioproducts: putting principles into practice. European Journal of Pharmaceutics and BioPharmaceutics. 1998, 45(3) 221-229.

29.   Tsuka H., Mori H., Okada K., Matsukawa S., Utilization of the freeze-drying method in the preparation of biologically active, intact RNA from hard frozen tissues of human prostate. Analytical Biochemistry. 1997, 247(2) 458-461.

30.   Kreilgaard L., Frokjaer S., Flink J.M., Randolph T.W., Carpenter J.F., Effects of additives on the stability of recombinant human factor XIII during freeze-drying and storage in the dried solid. Archives of Biochemistry and Biophysics. 1998, 360(1) 121-134.

31.   Kommawar S.S., Bakal R.L., Dewani A., Chandewar A.V., Research Journal of Pharmaceutical, Biological and Chemical Sciences.

32.   Ratti C., Hot air and freeze-drying of high-value foods: a review, Journal of food engineering, 2001, 49(4)311-319.

33.   https://nutrineat.com/freeze-drying-food-advantages-disadvantages

34.   Konan Y.N., Gurny R. and Allémann E., Preparation and characterization of sterile and freeze-dried sub-200 nm nanoparticles. International Journal of Pharmaceutics. 2002, 233(1-2) 239-252.

35.   Ohsawa T., Miura H. and Harada K., A novel method for preparing liposome with a high capacity to encapsulate proteinous drugs: freeze-drying method, Chemical and Pharmaceutical Bulletin.1984, 32(6) 2442-2445.

36.   Corveleyn S. and Remon J.P., Formulation of a lyophilized dry emulsion tablet for the delivery of poorly soluble drugs. International Journal of Pharmaceutics, 1998, 166(1) 65-74.

37.   Da KH, Sa AI, Na PC, Va CH. Formulation and Evaluation of Amphotericin-B as a Lyophilized Product.

38.   Dani B.A., Lyophilised antibody formulations, US Patent US20100226928A1, 2019.

39.   http://www.biotechnologynotes.com/food-biotechnology/food-technology/industrial-freeze-drying-process-applications-advantages-disadvantages-food-technology/14221

40.   Reckless., Na W., Chaobin Z., Juan W., Plant extract vacuum freeze drying device, China Patent CN208244130U, 2018.

41.   Ahmed I.S., Nafadi M.M and Fatahalla F.A., Formulation of a fast-dissolving ketoprofen tablet using freeze-drying in blisters technique, Drug Development and Industrial Pharmacy. 2006., 32(4) 437-442.

42.   Risbud M.V., Hardikar A.A., Bhat S.V., Bhonde R.R., pH-sensitive freeze-dried chitosan–polyvinyl pyrrolidone hydrogels as controlled release system for antibiotic delivery. Journal of Controlled Release, 2000, 68(1) 23-30.

43.   Jing W., Xuanyu S., A kind of bendamustine hydrochloride freeze-dried powder needle and preparation method thereof, China Patent CN108078931B, 2019.

44.   Fan P., Na L., Zhenya D., Xiang H., Jinli C., Xinbing P., Jingxia H., A kind of process units of Loratidine freeze-drying tablets, China Patent CN208469125U, 2019.

45.   Hamamoto, Y., Method for producing freeze-dried rice, Japan Patent JP6469906B1, 2019.

46.   Jiao Z., Guoquan L., Contains freeze-drying strawberry grain granules, China Patent CN207444208U, 2018.   

47.   Zhaojian L., Xiaogiu  S., Ying l., Qingguo S., The energy-saving fresh freeze drying system of low dew point air supply, China Patent CN208901523U, 2019.

48.   Chuansheng W., Jin L., A kind of medicinal material freeze drying plant, China Patent CN208620706U, 2019.

49.   Wei Y., A kind of bigger surface continuous discharge freeze-drying apparatus, China Patent CN208720639U, 2019.

50.   Xianglin., Liang T., A kind of freeze dryer with automatic feeder, China Patent CN208952541U, 2019.

51.   Xiaobo C., Peibin W., Yanlong L., A kind of low energy consumption freeze dryer, China Patent CN208382727U, 2019. 

52.   Maobin S., Xingbo L., Bi Z., Kuan W., Freeze -drying box, China Patent CN207610462U, 2018.

53.   Kuan, W., Cooling system of freeze -drying box body, China Patent CN207335290U, 2018.

 

Accepted on 13.11.2019           © RJPT All right reserved

Research J. Pharm. and Tech 2020; 13(5): 2468-2474.