features of preparation of the some parenteral dosage forms. technology of the emulsions and...

Features of preparation of the some parenteral dosage

forms. Technology of the

emulsions and suspensions.

Plan1. Infusion solutions.

2. Classification of the infusion solutions.

3. Requirements for the infusion solutions.

4. Emulsions and suspensions for injections.

5. Emulsions for a parenteral nutrition.

6. Technology of the emulsions and suspensions.

7. Equipment for emulsions and suspensions production.

Infusions (plasma-substituting preparations ) are sterile, aqueous solutions or emulsions with water as the continuous phase. They are free from pyrogens and are usually made isotonic with respect to blood.

They are principally intended for administration in large volume.

Intravenous infusions do not contain any added antimicrobial preservative.

Solutions for intravenous infusion, examined under suitable conditions of visibility, are clear and practically free from particles.

Classification of the infusion depend on the therapeutic action

1. Hemodynamic or shock-preventive drugs.

2. Antitoxic solutions. 3. Regulators of water-saline balance

and acid-base equilibrium. 4. Preparations for parenteral nutrition. 5. Oxygen-transferring solutions. 6. Multifunctional solutions.

Hemodynamic or shock-preventive drugs

They are intended to treat a shock of various origin and recover main functions of body homodynamic.

This group includes Polyglukin, Reopolyglukin, Gelatinol, Reogluman etc.

Antitoxic solutions

Many diseases are accompanied by body intoxication (infectious diseases, extensive burns, kidney and liver insufficiency, poisoning, etc.).

For their treatment it's necessary to use antitoxic solutions, which components should bind toxins and quickly eliminate them from an organism.

This group includes Polyvinylpirollidon, Polyvinyl alcohol, Hemodes, Polydes, etc.

Regulators of water-saline balance and acid-base

equilibrium

These solutions correct composition of blood at fluid loss, caused by diarrhea, brain edema, toxicoses, etc.

They include 0,9% and 10 % saline injection solutions of sodium chloride,

Ringer's and Ringer-Lock's solutions, Petrov's liquid, 4,5-8,4 % solutions of sodium hydrocarbonate,0,3-0,6 % solution of potassium chloride, etc.

Preparations for parenteral nutrition

They serve for maintenance of energetic resources of an organism, delivery of nutrients into bodies and tissues, especially after surgery procedures, at comas and other conditions when patient cannot take food normally.

Given group includes 40 % glucose solution, casein hydrolysate, Aminopeptidum, Amincrovinum, Fibrinosol, Lipostabile, Lipidine, Lipofundinum, Introlipid, Aminophosphatide, etc.

Oxygen-transferring solutions

They are intended to recover respiratory function of blood, and represented by compounds.

This group of infusion preparations is still in stage of research and development.

Multifunctional solutions

These preparations having a wide range of action can combine some of abovelisted functions.

Requirements for the infusion solutions

All common requirements for injection solutions : apyrogenety, sterility, stability, absence of mechanical inclusions,Additionally,1. absence of toxicity and possibility of accumulation,2. should be isotonic,3. should be isoionic,4. should be isohydric,5. their viscosity should be equal to viscosity of blood

plasma.

An emulsion

is usually defined as a system in which one liquid is relatively distributed or dispersed, in the form of droplets, in another substantially immiscible liquid.

The emulsion formation is a result of the co-production of water from the oil reservoir.

A pharmaceutical suspension is

a coarse dispersion in which internal phase is dispersed uniformly throughout the external phase.

The internal phase consisting of insoluble solid particles which is maintained uniformly through out the suspending vehicle with aid of single or combination of suspending agents.

The external phase (suspending medium) is generally aqueous in some instance, may be an organic or oily liquid for non oral use.

Classification of suspensions:

- Oral suspension e.g. antacid, antibiotic

- Externally applied suspension e.g.lotion

- Parenteral suspension

- Ophthalmic suspension

Features Desired In Pharmaceutical

Suspensions

1. The suspended particles should not settle rapidly and sediment produced, must be easily re-suspended by the use of moderate amount of shaking.

2. It should be easy to pour yet not watery and no grittiness.

3. It should have pleasing odour, colour and palatability.4. Good syringeability.5. It should be physically, chemically and

microbiologically stable.6. Parenteral/Ophthalmic suspension should be

sterilizable.

Parenteral suspension

suspensions are intended for administration only by injections;

suspensions have long time action; on completeness of effect renders influence the solvent and

size of particles of dispersing phases; suspensions should be prepared in aseptic conditions (A

class room by the GMP classifications of rooms cleanliness); active substances should be suspended with Water for

injections; for improvement of suspending process and increasing of

stability can be used ultrasound devices; suspensions may show a sediment which is readily

dispersible on shaking; for quality control of suspensions in addition check the

particles size.

Methods of suspension preparation:

1. Use of controlled flocculation

2. Use of structured vehicle

3. Combination of both of the two pervious

methods

Method of structured vehicle

These structured vehicles entrapped the particle and reduces the sedimentation of particles.

Thus, the use of deflocculated particles in a structure vehicle may form solid hard cake upon long storage.

High viscosity isn’t desirable:a - it causes difficulty in pouring and administration;b - it may affect drug absorption since they adsorb on the surface of particle and suppress the dissolution rate.

Structured vehicle is not useful for Parenteral suspension because they may create problem in syringeability due to high viscosity.

Method of Controlled flocculation

Controlled flocculation of particles is obtained by adding flocculating agents, which are:

1 - electrolytes

2 - surfactants

3 - polymers

Method of Flocculation in structured vehicles

Sometimes suspending agents can be added to flocculated suspension to retard sedimentation.

Examples of these agents are:

Carboxymethylcellulose (CMC), Carbopol 934, Veegum, and bentonite

Evaluation of suspensionsby determining their physical

stability:

Two useful parameters for the evaluation of suspensions are:

A - sedimentation volume

B - degree of flocculation

The determination of sedimentation volume provides a qualitative means of evaluation.

A quantitative knowledge is obtained by determining the degree of flocculation.

Technology of the suspension:

1. Preparing of the solvent and medicines substance (sterilization).

2. Dispersing of sterile substances in the sterile filtered solvent.

3. Filtering of the suspension by special filter.

4. Filling and labeling.

Equipment for suspension production

Reactors with agitator

Blade agitator - the simplest type of agitators; efficiency is low - mixing occurs around the axis of the blade.

Propeller agitator - the rate is relatively high, uniform of mixing is achieved by the formation of vorticity, which capture solution from the periphery. Power is low.

Planetary agitator – is used for mixing large amounts of fluids.

Speed is low. Mixing occurs throughout

the volume.

Frame agitator - looks like a frame with holes on the shaft. The rotation is carried out around the axis. It is used for mixing of the large volumes solution with high density.

Turbine agitator - high speed of rotation, so is not only mixing but grinding (dispersion) of solid particles, oil is carried out. It is used to obtain tinctures, emulsions, aromatic waters.

Anchor agitator – is used for mixing system of high viscosity. High power operation, the blades are placed close to the walls of reactors for better mixing.

Vibration agitator - perforated disk.

It is used in the production of emulsions, oil-bearing solutions.

When mixing dispersing of the oil droplets is carried out.

Drum agitator - drum, like a wheel for the squirrel. These agitators provide intensive mixing of liquids. To prepare emulsions and suspensions height of the vessel filling should be in 10 times greater than the diameter of the drum.

Disc agitator consist of two discs, fixed by a small distance from each other on a vertical shaft and rotating at high speed.

Each disc are flat and has a special shape and the holes, narrowed to the periphery.

When rotating disks layers of fluid under the lower disc, rising at high speed along the axis, and fluid layers that are above the upper disk, fall down along the axis.

Collision causes vortex flow around the volume of fluid that provides intensive mixing.

Used for mixing particles of solid materials with viscous liquids or liquids with different specific gravity.

Ultrasonic influence

is used in some cases to improve quality of a final product, promoting additional crushing and dispersing of a medicinal substance within a solvent, and on the other hand making dosage form sterile.

In such conditions size of particles decreases down to 1-3 microns and such suspensions or emulsions are suitable for introduction into a blood channel.

To increase stability of suspensions and emulsions cosolvents, stabilizers, emulgents and preservatives are used.

Emulsions for a parenteral nutrition.

- fatty emulsions for intravenous introduction. Preparations of dispersed fats for a parenteral feed exhibit the highest power value in comparison with protein and carbohydrate infusion drugs that facilitates composing of parenteral rations avoiding undesirable increase in volumes of liquids administered.

Fatty emulsions are considered as sources of essential lipids for an organism and mandatory components of a parenteral feed.

Emulsions for a parenteral nutrition.

Particles size of dispersed oil in emulsions is several times less than diameter of erythrocytes (7-8 microns).

Most of particles have size of 0,5 – 1,0 microns, that corresponds to size of blood chilomicrons.

Optimum particle size is achieved by methods of mechanical and ultrasonic dispersing.

Composition of Fatty emulsions

- Vegetative oils and phospholipids which contain a significant amount of essential polynunsaturated fatty acids (linoleic, linolenic, arachidinic) playing an important role in metabolism, make structural elements of cell membranes and precursors of tissue hormones – prostaglandins.

Composition of vegetative oils includes liposoluble vitamins A, D, E, K.

Properties of the fatty emulsion

Emulsion for parenteral feed can be related to drug formulations of the third generation as oil phase can incorporate some lipophilic drug substances, thus forming «microreservoris».

For stabilization fatty emulsions are provided with surfactants which form molecular layers around fatty micro drops.

Thus hydrophobic (lipophilic) radical are oriented into oil phase and hydrophilic ones into a water phase. In such liposome's can be created.

Emulsifier composition is designed depending on emulsion composition and concentration of neutral lipids.

Emulsifier for emulsions

Most frequently phospholipids obtained from egg yolk, cattle brain, sunflower, soya are used as emulsifier.

These are such which contain phosphatidylcholine, a sphingomyelin, phospatidyl-ethanolamine, phosphatidyl serine.

Phospholipids practically don't exhibit pharmacological action, but are useful to an organism.

Being stabilizers, they are simultaneously essential substances for weakened organism of a patient.

Emulsions for injections include the following groups:

Emulsions for parenteral nutrition (have higher power value in comparison with aqueous parenteral preparations)

Antihemolitic emulsions (consist phosphatidilaethanolamin, which detain of hemolis)

Emulsions for updating a blood

Peculiarities of manufacturing of emulsions for injections

For preparing of emulsions used mechanical and ultrasound dispersing.

Typical emulsion consists : Plants Oil 10 – 20 % Phospholipides 1,2 % Isotonic agents (Glyceroln, Xyilit, Sorbite) Water for injections

Infusion drugs,produced by freezing.

Ready sterile solution in the container is frozen and stored at a temperature -20 ° C. After defrost solutions are immediate used within 24 hours or short term storage at 2-8 ° C.

They are applied to get ready to use infusion solutions with insoluble cephalosporin antibiotics and antibiotics of other groups.

Available in 0.9 % sodium chloride or 5 % glucose solution in special containers «Galaxy» or «Viaflex» capacity of 50 and 100 ml.

Concentrates for intravenous infusion.

Sterile solutions intended for infusion after dilution with appropriate volume of this liquid.

After dilution resulting solution must meet the requirements to infusion solutions.

Additional requirements for concentrates: compatibility with solvents used for diluting; stability after dilution; possibility of intravenous administration.

Lyophilized forms of parenteral use.

Lyophilized preparations is sterile, porous powders containing a small amount of water and placed in a sterile container.

Injectable solutions of lyophilized substance are prepared at the bedside using sterile solvent which is added to the package.

When shaking a specified volume of the sterile liquid lyophilized material quickly form a transparent, free from mechanical particle, solution which must meet the requirements to parenteral drugs.

When drying by sublimation minimum chemical transformations of substances, thereby the number of destabilizing factors decrease and the stability and quality of the drug increases.

The process of lyophilization is carried out in aseptic conditions and divided into four stages:

1. Preparation of the material for sublimation (filling of aqueous solutions of ampoules, vials, beam forms, etc.)

2. Freeze the prepared material;3. Actually sublimation drying;4. Processing of the liophilizated product (sealing of

vials, ampoules and sealing following distribution of lyophilizate).

Frozen material with containers is placed in sublimation camera that is hermetically closed.

In the camera a vacuum is created and simultaneously raise the temperature.

These conditions are ideal for sublimation of water vapor without raising the temperature of the material and without transition of the pair in liquid state.