A REVIEW ON LYOPHILIZATION: A TECHNIQUE TO IMPROVE STABILITY OF HYGROSCOPIC, THERMOLABILE SUBSTANCES

Pharma Admission

Pharma courses

pharma admission

pharma courses

 

{ DOWNLOAD AS PDF }

ABOUT AUTHORS
SHIVANAND *, SAYANTAN MUKHOPADHAYAY
Division of Pharmaceutical Sciences S.G.R.R.I.T.S
Dehradun, Uttarakhand  248001, India.
*shiva3671@gmail.com

ABSTRACT:
The active pharmaceutical ingredient that is thermolabile and moisture sensitive in nature generally degraded in atmospheric condition and thus have reduced stability and self-life. Lyophilization is one of those techniques which is utilized effectively to improve such critical condition. It is the one of the emerging technology in themodern era, which is effectively involved in the preparation of several antibiotics (e.g., chloramphenicol, doxycycline) and anti-cancer drugs (e.g., doxorubicin, epirubicin). This technique effectively utilized the phenomenon of sublimation to obtained primary dried product followed by removal of excess amount of moisture by modulation of heat. This technique not only improved self-life of thedrug but also provides fast reconstitution and reduced the cost of storage and shipping. Inthis review article principle behind lyophilization, steps involved, formulation aspects, theimportance of lyophilization and detection of the end point in lyophilization along with recent advancementwas explained.

Reference Id: PHARMATUTOR-ART-2535

PharmaTutor (Print-ISSN: 2394 - 6679; e-ISSN: 2347 - 7881)

Volume 5, Issue 11

Received On: 10/07/2017; Accepted On: 14/07/2017; Published On: 01/11/2017

How to cite this article: Shivanand A, Mukhopadhayaya S; A Review on Lyophilization: A Technique to Improve Stability of Hygroscopic, Thermolabile Substances; PharmaTutor; 2017; 5(11); 28-39

INTRODUCTION
Lyophilization or Freeze-Drying Technique
Lyophilization is the most common technique for the manufacturing of parenteral pharmaceutical product when the product is unstable in aqueous solution. It is helpful in long-term storage and makes the product stable, for ensure the stability of sterile product require low moisture content about less than 1% for the preservation of the pharmaceutical product. Lyophilization or freeze drying (FD) mainly involved in the removal of solvent (water) from the pharmaceutical product. In this process, thefirst Solvent is in a frozen state (solid) and then water is removed by sublimation process in a vacuum chamber. The Lyophilization technique mainly consists of three unique, separate, & interdependent processes; freezing, primary drying (sublimation), and secondary drying (desorption).[1, 2, 3]
The use of physical phenomenon for sublimation, which mainly involves the direct conversion solid state (ice) to the gaseous state. Freeze-drying is an effective technique for drying the pharmaceutical product without changing the product properties. In the lyophilized parenteral formulation, water is used as a main component. Hydrolysis is the most common instability mechanism of parenteral. In as much as, lyophilization technique is widely used for preservation of sensitive molecules from degradation (example- water sensitive &thermolabile) and improves long term storage. The final product makes easy reconstitution and restoration to solution form.Lyophilizationis a drying process used in the manufacture of pharmaceuticals and biologicals product those are thermolabile or unstable in aqueous solutions and make the product storage for a prolonged time. [4, 5]

Characteristics, advantages and disadvantages of Lyophilized Product[6, 7, 8]
Characteristics
• Long stability of the product.
• Minimal reconstitution time.
• Elegant cake appearance.
• After reconstitution maintains original dosage form characteristics, including solution properties; structure and conformation of a pharmaceutical product, proteins, and particle-size dispersion in suspensions.
• Isotonicity is maintained after reconstitution of the product.
Advantages
• Chemical decomposition is minimized.
• Without excessive heating water is removed from the product.
• In a dry condition enhances product stability.
• Dissolution is fast for reconstituted products.
• From thermosensitivematerial, water can remove without changing the molecule's properties.
• A lyophilized product having the high specific surface area, which helps rapid and complete rehydration of the solid.
• In vials, freeze-dried dosage forms filled as a solution, which makes more easy and precise filling than powder in to vials.
Disadvantages
• The requirement of sterile diluents for reconstitutionof the product.
• Many pharmaceutical drug and biological products such as vaccines, liposomes, and protein are damaged by freeze-drying during process time.
• Stability of a drug in the solid state mainly depends on its physical state of molecules.
• Time increases for processing and Handling.
• By using vacuum method volatile removed from the product.
• Processing time, Cost and complexity of equipment increased

 

Applications of lyophilization
There are several applications of lyophilization or freeze-drying method used in the manufacturing of pharmaceutical and a biological product. Lyophilization is used in the pharmaceutical industry, for the production of
• Injectable drug product.
• Solid oral dosage forms (Example- Ondansetron-rapid orally dissolving tablets).

 

Methods of Lyophilization
Depending on the type of product requirement different drying technique may be used. Several different lyophilization methods are respectively
• Manifold drying
• Batch drying
• Bulk drying

Manifold drying
In this lyophilization methods, froze solid (ice) vials or flasks individually attached to the drying chamber ports. This method is generally used for products having a high collapse or eutectic temperatures with small volumes. The advantage of this method is that since each vial or flasks direct connected with the collector. Hence, the drying process is relatively faster as compared to the other drying method and enhance the drying efficiency. Since each vial or flask is attached individually to the drying chamber, it can be removed from drying chamber without interrupting the other flasks or vials.[ 9]

Batch drying
In this lyophilization methods, used for the drying of a large number of vials having similar size and contain the same drug product. It having the potential to the control of temperature and pressure. Since all the vials were kept at the similar drying chamber (controlled temperature and pressure), the variability of the product is minimized. This batch drying method is widely used in the pharmaceutical industry.[10]
Bulk drying

In this lyophilization methods, the product is directly poured in a single unit in a tray and placed the tray in a drying chamber, this method is known as bulk drying. The product doesn’t uniform dried. Hence, the product doesn’t lend sealed in the aseptic area. Usually after removal of the product from equipment packed in air tight containers. This drying process is generally for those products that are not sensitive to moisture or oxygen.[11]

Principle behind freeze drying
The main principle behind freeze drying process is known as sublimation, in the sublimation process water is directly converted from solid state (ice) to the vapor phase without goes into a liquid state. At below triple pointsublimation of water can take place at particular temperature and pressures. The liquid to be first frozen solid (ice) and frozen solid to be placed in a high vacuum chamber to heat (by using radiation or conduction or by both). Hence frozen liquid sublimes leaving behind the only solid product or a dried product of the original liquid. The driving force for removal of water during lyophilization is the concentration gradient of water vapor between the drying front and condenser.
To remove the water from formulation, the lyophilization or freeze-drying process consists of;
• Froze the formulation into solid (ice).
• By sublimation process, the solid (ice) directly converted into vapor by using a vacuum chamber.
• Remove the water vapor by using a condenser. After removal of water from the formulation, the freeze-dried product can be removed from the machine.

Fig .1:Phase diagram of water triple point.[39]

The triple point of any substance is the temperature and pressure at which the three phases (solid, liquid, and gas) of that substance coexist. The phase diagram of water shown in Fig. 1. Water have three physical states at a particular temperature and atmospheric pressure (example-pressure 0.611657 kPa or mbar 0.00603659 atm & temperature 273.16 K or 0.01 °C).[1, 7, 12] The principle behind freeze or lyophilization is sublimation is based on its physical phenomena. The solid (ice) in the product is directly transformed into water vapor phase without going into a liquid state. If the partial water vapor pressure is lower than the partial pressure of the solid (ice) then the solid become avapor at this relevant temperature.[13]The vapor pressure over ice chart data shown in Table. 1.

Vapor pressure over ice chart

Temperature

Vapor Pressure

Temperature

Vapor Pressure

Deg C

mTorr

mBar

Deg C

mTorr

mBar

0

4,584.00

6.111480

-50

29.500

0.039330

-2

3,883.00

5.176893

-52

23.000

0.030664

-4

3,281.00

4.374295

-54

17.900

0.023865

-6

2,765.00

3.686353

-56

13.800

0.018398

-8

2,325.00

3.099737

-58

10.600

0.014132

-10

1,949.00

2.598446

-60

8.100

0.010799

-12

1,630.00

2.173149

-62

6.160

0.008213

-14

1,359.00

1.811846

-64

4.660

0.006213

-16

1,130.00

1.506539

-66

3.510

0.004680

-18

936.80

1.248960

-68

2.630

0.003506

-20

774.40

1.032446

-70

1.960

0.002613

-22

638.20

0.850861

-72

1.450

0.001933

-24

524.30

0.699007

-74

1.060

0.001413

-26

429.40

0.572485

-76

0.780

0.001040

-28

350.50

0.467294

-78

0.570

0.000760

-30

285.10

0.380101

-80

0.410

0.000547

-32

231.20

0.308240

-82

0.290

0.000387

-34

186.80

0.249045

-84

0.210

0.000280

-36

150.30

0.200383

-86

0.150

0.000200

-38

120.60

0.160786

-88

0.100

0.000133

-40

96.30

0.128389

-90

0.072

0.000096

-42

76.70

0.102258

-92

0.049

0.000065

-44

60.80

0.081060

-94

0.034

0.000045

-46

48.00

0.063995

-96

0.023

0.000031

-48

37.70

0.050262

-98

0.015

0.000020

Steps involved in freeze drying process

The freeze-drying process mainly consists of three stages.Fig. 2 demonstrate that the steps involved in freeze drying process.
• Freezing
• Primary drying
• Secondary drying

Fig. 2: Steps involved in the process of freeze drying.[1]

NOW YOU CAN ALSO PUBLISH YOUR ARTICLE ONLINE.

SUBMIT YOUR ARTICLE/PROJECT AT editor-in-chief@pharmatutor.org

Subscribe to Pharmatutor Alerts by Email

FIND OUT MORE ARTICLES AT OUR DATABASE


 

Pages

FIND MORE ARTICLES