Sunday, 9 July 2017

FORMULATION OF PARENTRALS: PHARMACEUTICS (NOTES FOR GPAT PREPARATION)

Formulation of parenterals is an important topic keeping in view the preparation of the GPAT. In this topic you will in detail about the formulation of parenterals and their quality tests. 

Parenterals are defined as the dosage form which are administered other than the oral route. Below are the important basic points to be considered:


  • Maximum volume for single dose container for parenteral administration is limited to 1000 ml/ 1Litre.
  • Maximum volume for intradermal/intracardic, intra arterial administration is 0.2 ml.

  • Maximum volume for intramuscular administration is 10 ml .

  • Maximum volume for intraspinal, intracardiac, intra arterial administration is 10 ml
  • Maximum volume for intravenous administration is 1liter      
  • For intraorneal ,sub-conjuctival, intravitreous volume should not exceed more than 1 ml  
  • Volume not more than 20 ml  should be administered by syringe  
  • Parenteral suspension should not be given by intravenous (danger of blockage of small blood vessels)and subcutaneously (very painful and irritating).
  • HYALURONIDASE sometimes used an adjunct to increase the absorption of injected drug.  

VEHICLES FOR STERILE PREPARATIONS

Water is the most commonly used as the vehicle. Quality tests for water for injection are as follows:

a) Total solid content: Not more than 10 ppm.
b) Gravimetric analysis: For dissociated and undissociated organic and inorganic substances.
c) Electronic measurement of conductivity: should not be more than 0.1 ppm of NaCl/ 1 microhm.

Co-solvent like [Diloxanes, dimethyl  acetamide,ethyl alcohol, PEG 400 and 600 are used when the drug dissolved in water undergoes hydrolysis, oxidation ,decarboxylation , and racemization which markedly affected by ph of the solution 

  • Epinephrine undergoes recemization and oxidation , but if the ph bf the solution is maintained at ph of  the solution is maintained at pH less 3 little reaction occurs. The oxidation reaction can be reduced by displacing atmospheric oxygen with inert gas or adding 0.15% Sodium Metabisulphite as an antioxidant.
  • Atropine sulfate rapidly hydrolyses in aqueous solution but if pH 3-4 is maintained than little reaction occurs.
  • Barbituric acid and its derivatives hydrolyzed rapidly in water particularly at low pH.
Ethyl alcohol for c.glycosides, propylene glycol for barbiturates, propylene glycol for alkaloids and certain antibiotics, ethylenediamene to solublize theophylline, sodium benzoate to solublize caffeine, glycerol to solublize ergotamine is used.

         
Water immiscible solvents:                            
  • Fixed oils,ethyl oleate , isopropyl  myristate, benzyl  benzoate, sesame oil and cotton seed oil are the water immiscible solvents used. 
  • Most widely used nonaqueous solvent are propylene glycol and polyethylene glycol.  

ADDITIVES USED IN PARENTERALS


1. Local anesthetics:
  • Benzyl Alcohal and procaine in parenteral is commonly used as local anesthetic.

2. Antioxidant:
  • Prevent antioxidation: Ascorbic acid , gallic acid , etc.
  • Reducing agents: Sodium bisulfite , sodium metabisulfite, thiourea
  • Blocking agents: Ascorbic acid ,BHT,BHA. BHA and BHT are mostly used in non – aqueous parenteral preparation .
  • Synergists: Citric acid , tartaric acid , citraconic acid

Sodium bisulfate can be absorbed from peritoneal dialysis solution. So it generally NOT used as antioxidant in  intraspinal injection.

3. Buffer:
  • Citrates (pH 2-6).
  • Acetates (pH 4-6)
  • Phosphates (pH 6-8)

4. Tonicity modifiers: 

Isotonicity is most important for intraspinal injection and intravenous .
  • For rapid absorption of drug intramuscularly a hypertonic solution is used because increase the effusion rate of tissue fluids.
  • The compounds contributing to the isotonicity of a product reduce the pain of injection in the area with nerve ending . 
  • Sorbitol , mannitol , lactose, glycerin, and sodium sulphate is mainly used as tonicity modifiers.

5. Solubilizer ,wetting agents or emulsifiers:
  • Lecithin, polysorbate 80 (tweens)], sodium dexo cholate, theophylline

6. Stabilizer: 
  • Creatinine , glycine , sodium caprylate

7. Chelating agents:
  • Disodium or calcium disodium salt of ethylene diamine tetra acetic acid.
  • Thiomerosal a bacterostatic agent used in polimyelitis vaccine as vaccine is unstable in pressure of cupric ions and the brekdown of product destroys the antigenicity of the vaccine .
  • Sometimes complexation may occur between added ingredient and macromolecule.E.g polysorbate 80 can form complex with methyl and propyl esters of p –hydroxybenzoic acid, reducing the antibacterial activity.

PLASTIC CONTAINERS USED IN PARENTERALS


  • Polypropylene and polyethylene are most widely used in parenterals plastic containers.
  • low density polyethylene and polystyrene are generally not autoclavable. 
  • Polyamides and polystyrene have high reactivity due to sorption as they have high premeability for water vapors.
  • Flexible polyvinyl chloride is used for intravenous solution
  • Polyethylene containers for opthalmic solution
Glass containers: Principally glass in silicon dioxide tetrahedron is used.

PARENTERAL SUSPENSION


  • Solid content is 0.5-5% but may go up to 30%  in antibiotic preparation .
  • Stabilizing agent used to reduce the interfacial tension between the solid and vehicle is polysorbate 80 and lecithin.
  • For increasing the viscosity of parenterals suspensions mainly sorbitol and protective colloid is used.
  • To increase the stability of flocculated parenterals suspensions monosodium citrate is added. 

PARENTERAL EMULSION

  • Uniform droplets 1U -5U in size of internal phase. 
  • Mostly emulsifier used in parenterals emulsion are oxyethyleneoxypropylene polymer and lecithin.

OSMOLALITY and OSMOLARITY

  • Solution that have same osmolarity as that of RBC are isotonic, unit of osmolarity are osmols/millosmoles/ mosmol. 
  • Osmolarity measure the osmotic potential of a solution i.e. potential to move water through semi-permeable membrance from a solution of lower osmotic potential.[osmolarity of plasma as reported is 306mosmol/liter]. 
  • Intravenous injection with hypotomic solutions cause swelling of erythrocytes and hemolysis while hypertonic solution can cause crenation of erythrocytes. 
  • Glucose 5 % infusion has osmolarity 280 mosmol/ liter and sodium chloride an osmolarity 308 mosmol/ liter . 
  • If parenterals solution is hypotonic then osmolarity adustment is made by NaCl, glucose , mannitol to make isotonic.

 QUALITY CONTROL TESTS FOR PARENTERALS

1. LEAKER TEST : 
  • This is test is done to detect in completely sealed ampules. 
  • Leakers usually detected by producing pressure with an incompletely sealed ampule in a vaccum chamber ,ampules are submerged in deeply colored solution of 0.5%  - 1%  METHYLENE BLUE.
2. PYROGEN TEST : 
  • Endotoxin (Endotoxins are a class of pyrogen which are lipopolysaccrides, soluble in water and are components of the cell wall of gram –negative bacteriadetection was accomplished by injecting rabbit with the sample and observing the pressure the response in their body temperature.
3. LAL ( Limulus amoebocyte lysate) test:
  •  In vitro test ( 5-10 time more sensitive than rabbit test )method of pyrogens. 
  • This test is based on observation that horseshoe crab blood is mixed with a sample suspected of endotoxin contamination , and a reaction is observed if endotoxins are present( 60 min when incubated at a 37 degree C) .
  • Amount of turbidity occurred is the measure of the amount of pyrogens present.
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You can also check our other sections which will help you in your preparation:

5.  Miscellaneous topics for GPAT

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