Lyophilized injection: A modern approach of injectable dosage form

ABSTRACT 

Now-a-days, lyophilized injection dosage form is extensively used to improve the bioavailability, stability, solubility and patient compliance. The lyophilized injection is used for better patient compliance especially in bed ridden patients and for attaining maximum bioavailability, improved stability. The lyophilized injection reconstitutes before injection to produce liquid injection. This review includes a detailed updated concept on lyophilized injection.

Keywords: Lyophilized injection, parenteral, freezing, sublimation, desorption freeze drying

INTRODUCTION

Lyophilization, or freeze-drying, is a crucial process technology for many parenteral drugs, and an essential part of extending product shelf life. Lyophilization is a water removal process through which perishable items are preserved. This process boosts the shelf life of the material and also makes them easier to transport. Lyophilized injections are also prescribed to attain maximum bioavailability and stability in patients suffering from a number of diseases. In lyophilization procedure, vacuum takes place at very low pressures so that the operation occurs below the triple point of water. With a flood of protein-based therapeutics and other injectable products in the drug development pipeline—it is expected that many approved new molecular entities (NME’s) in the coming  years will require lyophilization—there is a real need for leaner, more efficient freeze-drying methods[1] 

PRINCIPLE

The main principle involved in freeze drying is a phenomenon called sublimation, where water passes directly from solid state(ice) to the vapor state without passing through the liquid state.

Lyophilization is carried out using a simple principle of physics sublimation. Sublimation is the transition of a substance from the solid to the vapour state, without first passing through an intermediate liquid phase.

Lyophilization is performed at temperature and pressure conditions below the triple point, to enable sublimation of ice.

The entire process is performed at low temperature and pressure by applying vacuum, hence is suited for drying of thermolabile compounds.

The concentration gradient of water vapour between the drying front and condenser is the driving force for removal of water during lyophilization.

STEPS INVOLVED IN LYOPHILIZATION^2,5,6,7

Freezing Stage

During freezing, material is cooled below its eutectic point, the lowest temperature at which the solid and liquid phases of the material can coexist. The most suitable freezing technique for a specific product should be determined and its parameters ascertained prior to sublimation drying. The freezing behaviour of the product may be investigated, for instance, using the resistance-measurement method.

Two different freezing methods are used for pharmaceutical products: freezing by contact with cooled surface; or rotation/dynamic freezing in a coolant bath.

The first method is a static freezing technique in which a versatile freeze dryer must be capable of adjusting the freezing rate to the specific product and control the freezing speed. A final temperature of -50 °C will, in many cases, be sufficient to meet most requirements.

The second method is used whenever large quantities of a liquid product are to be frozen and dried in flasks or large bottles. The appropriate freezing technique will also deliver a frozen product that is suitable for sublimation; that is, uniform and as thin as possible to achieve a short drying time.

Primary Drying (Sublimation)

The main step in the lyophilization process, which easily removes moisture up to 98-99%. from the frozen product.

At the beginning of the primary drying phase, ice sublimation takes place at the product surface. As the process continues, the subliming surface withdraws into the product and the resulting vapour must be conducted through the previously dried outer layers. This means that the drying process depends on the speed of vapour transfer and removal, as well as the necessary heat of sublimation. The heat required for sublimation is supplied by convection and thermal conduction and, to a lesser degree, by thermal radiation.

Apart from heat transfer by thermal conduction and radiation, heat transfer by convection must be optimized. Whilst water vapour flows from within the product to the outside, heat transfer must go in the opposite direction. To avoid product damage, the maximum possible temperature for the dried product must not be exceeded. By contrast, care must be taken to maintain the required sublimation temperature throughout drying, keep the heat supply to the ice-core boundary in equilibrium and avoid overheating the sublimation zone. The primary drying phase continues until all the ice in the product has been sublimated.      

Secondary Drying (Desorption)

In the secondary or final drying phase, the residual moisture content is reduced as much as possible to ensure that the product is in a permanently storable state. The water bound by adsorption at the internal surface of the product has to be removed. To achieve this, it is often necessary to overcome water’s capillary forces. The freeze drying plant must therefore be designed to produce a high pressure gradient during the secondary drying phase (in most cases, it is not possible to raise the temperature without damaging the product). The secondary drying process must be precisely controlled to prevent over-drying the product.

Packing

After drying the vacuum is replaced by filtered dry air or nitrogen to establish atmospheric pressure. Ampoules are sealed by either tip sealing or pull sealing method. Vials and bottles are sealed with rubber closures and aluminium caps.[3,4]

ADVANTAGES OF LYOPHILIZATION^8,9,11

• The colour remains uniform throughout. 
• Has sufficient strength to last for a long time.
• Freeze-dried products are sterile and free from pyrogen.
• Free from particles.
• Enhanced stability of a dry powder.
• Removal of water without excessive heating of the product.
• Stable in dry and reconstitution stage.
• Rapid and easy dissolution of reconstituted product.

DISADVANTAGES OF LYOPHILIZATION

• Increased handling and processing time. 
• Many biological molecules are damaged by the stress associated with freezing, freeze -drying, or both.
• Volatile compounds may be removed by vacuum. 
• Need for sterile diluents upon reconstruction.

BENEFITS^10,12,13

For Unconscious Patients 

Since unconscious patients are unable to swallow tablets and capsules, lyophilized injections are the most preferred and convenient option for such patients.

Bioavailability is 100% 

In pharmacology terms, bioavailability refers to the degree and rate at which an administered drug is absorbed by the body’s circulatory system, in fact the systematic circulation. Lyophilized injections get easily absorbed in the patient’s system and hence their body gets equipped to quickly respond to the given dosage. 

RECENT DEVELOPMENT IN FIELD OF LYOPHILIZED FORMULATIONS¹⁴

Large number of works has been done in the pharmaceutical industries. Some of the recent findings are explained in the below table:

DRUG(S)	CATEGORY	ROUTE OF ADMINISTRATION
Amphotericin B & Cholestryl sulphate	Anti-fungal	IV Infusion at 2-4 mg/kg/hr
Chlorthiazide sodium	Diuretic & anti-hypertensive	IV Infusion bolus
Cisplastin	Anti-neoplastic	IV Infusion
Gemcitabine	Anti-neoplastic	IV Infusion over 30min
Thiopental sodium	Short acting anesthetic	IV Infusion

CONCLUSION 

Nowadays injectable dosage forms explore much more than other dosage forms because of more bioavailability, sterilization, patient compliance in geriatric and bed ridden patients and for fastest delivery of drugs to site of action. Drugs which are formulating as injectable dosage form which have lower stability in liquid form subject to lyophilization. Lyophilization is the technique of choice over than other drying techniques to improve the stability of injection by avoiding the moisture content. The lyophilized injection gave a stable and therapeutically effective formulation which provides extended shelf life. Lyophilization transforms a drug product from a liquid to a stable solid by removing water or other solvents. Drug developers are increasingly interested in this technique as it can to extend the shelf life of both small and large molecule drugs. Meeting the growing demand for lyophilization, also known as freeze drying, requires a high level of operational experience and practical expertise.

ACKNOWLEDGEMENT

The authors wish to thank Mr. Gaurav Tripathi, Works Manager, Mr. Sanjay Chauhan, Sr. Manager, Supply Chain, and Ms. Monika Tomar, Manager-R&D, Sigachi Industries Private Limited, Telangana, India for support.

FUNDING

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CONFLICT OF INTEREST

The author declares that he does not have any financial and personal relationships with other people or any other organizations that could inappropriately influence this research work.

QUERY

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REFERENCES

1.  Loyd V allen, Jr., Nicholas G.popovich, Howard C.Ansel. Ansel’s Pharmaceutical dosage forms and drug delivery systems, 9th ed.Philadelphia: Lippincott Williams & Wilkins; 2011. Section I, Introduction to drugs, drug dosage forms, and drug delivery systems, Chapter 2, New drug development and Approval process; p.27.
2.  Oetjen  G-W,  HASELEY  P.  Freeze-Drying.G.W.oetejen,  ed. Encycl Sep Sci Elsevier  Sci.2000; 1023-1034.
3.  USP, EP and JP Pharmacopoeia.
4. Michael.  J.  Akers Parenteral preparations, Chapter 26,Remington  Essentials  of Pharmaceutics  edited  by  Linda Felton,  p.495-5 . 
5. The science and practice of pharmacy by Remington,21 edition, vol-1.
6.  Leon Lachmen Herbert A liebeman,The theory and practice of Industrial Pharmacy.
7. Pharmaceutical Engineering-Principles and practice by C.V. S Subramanyam, J.Thimma Setty, Sarasija Suresh and V. kusum Devi.
8. Aulton’s Pharmaceutics -The Design and Manufacture of Medicines by Micheal E.Aulton.
9. The Lyophilization of Pharmaceuticals: A Literature Review by N.A.Williams and G.P.Polli.Journal of Pharmaceutical science and technology.
10. Pharma Solutions by Dr. Ajay “Strategies and Key challenges for Safe Parenteral preparation”.
11. Pharma Solutions by Dr. Ajay “Impurities in pharmaceutical products How, Why, Characterize and Acceptance criteria”.
12. Ajay Kumar Singh “Effect of Aqua- Organic medium on lon-dipole type Reactions” in ARJP.
13. Ajay Kumar Singh “A study of alkaline Hydrolysis of ethyl isonicotinate” in ARJP.
14. It is based on my personal experiment. 
15. Photo courtesy: Google

ABBREVIATIONS 

NME’s New Molecular Entities R&D: Research and Development, USP: United States Pharmacopoeia, EP: European Pharmacopoeia, JP: Japanese Pharmacopoeia, M.Sc.: Master of Science, PhD: Doctor of Philosophy.

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About the Author

Dr. Ajay Kumar Singh, M.Sc. (Gold Medalist), Ph.D. is the author and founder of “Pharma Solutions by Dr. Ajay”. For more helpful articles, please visit our blog. Need Help: Ask Question