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PREPRATION & STABILITY OF LARGE VOLUME PARENTERALS
PRINCE THAKUR
M Pharmacy {1st Year}
CONTENTS
A. Introduction.
B. Types of Large Volume Parentrals.
C. Preparation of Large Volume Parentrals.
D. Problems associated with Parentrals.
E. Stability Studies for Large Volume Parenterals
INTRODUCTION
Large volume parenterals solutions are employed in maintenance
therapy for the patient entering or recovering from surgery and for the patient who
is unconscious and unable to take Fluids, Electrolytes and nutrition orally.
These solutions may also be used in replacement therapy for patients who
have suffered a heavy loss of fluids and electrolytes.
These are having range about 100 ml – 1 litre.
These are delivered through IV-Route.
These are supplied in single large dose containers.
Maintenance Therapy
When patient is receiving parenteral These are
fluids for only a few days Simple solutions
Providing
adequate
amounts of water, dextrose
and
small amounts of Sodium
&.
Potassium
When patient are unable to take oral
nutrition slightly for Longer Periods
(3-6 days) High Caloric Content
solution given. Like
Carbohydrate
, Protein,
Fat.
Administration:
Large Volume Parenteral are slowly administered through a large vein such as
Superior Vena Cava , which is Beneath the clavicle and near the heart.
 About 10% dextrose solution given by superior vena cava.
Function:-
 This permits Rapid Dilution of the concentrated Hyperalimentation fluid and minimizes the risk
of tissue or cellular damage due to Hypertonicity of the solution.
TNAs(Three in one):
Total Nutrient Admixture include all substrate necessary for nutritional
support
Carbohydrates , Protein , Fat & Electrolytes.
In 1994(April) the FDA issued a safety alert regarding the hazards of precipitation associated with
Parenteral Nutrition.
2 deaths Reported 2 other cases of Respiratory distress
Because of TNAs(Formation of Calcium phosphate and deposition of its crystals in
Lung Tissue).
Calcium phosphate get precipitate in the admixture
FDA approves that filter be used(0.22 micron meter)
When infusing either central or peripheral parenterals nutrition admixtures
Filter having both Bacterial retentive and air- elimininating filters have been recommended for use with
Lipid Free(two-in-one) parenteral nutrient solutions
 Three-in-one Lipid Emulsion causes problem it obscures any precipitate.
 Thus, Two-in-one Lipid Emulsion are employed.
TYPES OF LARGE VOLUME PARENTRALS :
(A): Hyperalimentation Solution.
(B): Cardioplegia Solution.
(C): Peritoneal Dialysis Solution.
(D): Irrigating Solutions.
{1}: Hyperalimentation Solutions: It is a method of feeding patients by infusing a mixture of
all necessary nutrients into the circulatory system, thus Bypassing the GI-Tract.
 By these solutions, administrations of large amount of nutrients to patients who is unable to
take food orally for several weeks at caloric intake levels of 4000 kcal/day or more.
 Development of Subclavian vein cannulation- infused fluid is rapidly diluted by the high blood
flow in the subclavian vein.
 Commonly consist of mixtures of dextrose, amino acids & lipids, added electrolytes, trace metals
& vitamins
 Administration of life-saving or life-sustaining nutrients to comatose patients or to patients
undergoing treatment for esophageal obstruction, GI diseases (including cancer), ulcer.
Preparation & Stability of Large Volume Parenterals by PRINCE THAKUR
FORMULATION:
CONTENT SOURCES
• Calories Dextrose
• Nitrogen Crystalline amino acids
• Electrolytes Na, K , Cl, PO4
• Vitamins Water soluble, Fat soluble
• Elements Traces of Zn , Cu , Mn , Cr.
{2}: Cardioplegic Solutions: Large Volume Parenterals are used in Heart Surgery to prevent
injury to Myocardium during Reperfusion , as well as to maintain bloodless operating field.
 Reperfusion or Reoxygenation injury, it is the tissue damage caused when blood supply returns
to tissue after a period of lack of oxygen or ischemia.
 Sometimes called, Ischemia- Reperfusion Injury(IRI).
 It maintains the Diastolic arrest.
 Its administration in cold form(in order to cool the Myocardium and Minimize activity).
 Slightly Hypertonic & Alkaline to compensate metabolic acidosis and to minimize reperfusion
injury resulting from tissue edema.
Preparation & Stability of Large Volume Parenterals by PRINCE THAKUR
{3}: Peritoneal Dialysis Solution:
 Are infused continuously into the abdominal cavity, bathing the peritonium & are then
continuously withdrawn.
 To remove the toxic substances from the body or to aid & accelerate the excretion function
normal to the kidneys.
 The process is employed to counteract some forms of drug or chemical toxicity as well as to
treat acute renal insufficiency.
 Solution contain glucose & have an ionic content similar to normal extracellular fluid.
An antibiotic is often added to these solution as a prophylactic measure.
Cleansing fluid Tube inserted Inside Abdominal Dialysate absorb waste product
(Dialysate) (Catheter) Cavity from Blood vessels in
abdominal
lining
Discarded then
Preparation & Stability of Large Volume Parenterals by PRINCE THAKUR
{4}: Irrigating Solutions:
 Are intended to irrigate, flush, & aid in cleansing body cavities & wounds.
 Although certain IV solutions, such as normal saline, may be used as irrigating solutions
should not be used parenterally.(Because they enter in systemic circulation in relatively in
large volume).
 The Risk of dilutional states is inversely proportional to electrolyte concentrations of
administered Parenteral solutions.
 They must be sterile, pyrogen-free, & made & handled with the same care as parenteral
solutions.
 Also used in treatment of serious wounds infused into the Blood stream.
Preparation & Stability of Large Volume Parenterals by PRINCE THAKUR
PREPARATION OF LARGE VOLUME PARENTRELS:
[1]. Therapeutic Agents:- Antibiotics, Anticancer, Steroids, Vaccines, Antipyretic,
Analgesics, Anti-inflammatory & to know about the physical & chemical properties of the drug
molecule.
 LVP like Dextrose, NaCl, or combination etc.
[2]. Aqueous Vehicle:- According to USP , Water for Injection used which is highly sterilized.
 According to USP, it include not more than 10 parts per million of total solids(mg/L). pH (5.0-
7.0).
 Water for Injection is generally prepared by either Distillation or Reverse Osmosis.
Compression still: for production of LVP with Low consumption of energy on water.
Produce water 5- 10 times more cost effectively then Multiple effect
distillers.
PROCEDURE:- Boiling by heating elements turned ON As the water reaches near
boiling temperatures The Compressor Turns ON Steam is
pressurized which raises the steam temperature The pressurized steam gives off its
heat to the Tap Water inside the boiling chamber Causing water to boil
Steam will be condensed Which creates more steam this gives Latent
heat
HOT WATER produces(slightly cooler than boiling temperature)
One of the heating elements will cycle ON and OFF as per periodically need.
3. Sterile Water for Injection:-
 Single dose containers .
 It is hypotonic , non-pyrogenic , sterile made by distillation .
 It contains no anti-microbial or bacteriostatic , additives or
buffer.
 pH- (5.5-7.0).
 Not for IM , IV use because Hemolysis.
 It is used for washing wounds , surgical incisions or body tissues.
5. Water Miscible Vehicles:-
 As the name suggest , this occupies some part of the vehicle and it helps in decresing
hydrolysis and to solubilize some drugs.
Ex: Ethyl alcohol, Propylene glycol.
6. Non-Aqueous Vehicle:-
Ex: Fixed oils, peanut oils, corn oils , cotton seed oils , Sesame oils.
7. Anti-oxidants:- Protects formulation from oxidation & maintain the product stability.
Ex: (a) Reducing Agents: a substance that reduces a chemical compound usually by
donating electrons.
E.g ;
Ascorbic Acid, Thiourea.
(b) Blocking Agents: Tocopherol.
8. Surfactants:- Help to solublise the active ingredient.
• Polyoxythylene sorbitan mono-oleate.
• Sorbitan mono-oleate.
9. Tonicity Agents:- Formulation needs to be isotonic to avoid destruction of RBCs, Irritation,
and tissue damage.
More important for Large volumes , Rapidly administered and extra-vascular injections.
Reduces the pain on injection.
Ex: Sorbitan mono-oleate ,NaCl , KCl ,Dextrose solution.
10. Other Additives:-
Buffers: To stabilize the emulsion from chemical degradation.
To maintain the pH.
Ex: Citrate , Acetate , phosphate.
Bulking Agents: for freeze dried preparations(solids).
Ex: Mannitol, Lactose , Sucrose , Dextran.
12. Chelating Agents :-
Also used in Limited number.
Improve efficacy of Anti-oxidants.
To remove traces Elements that catalyse oxidative degeneration.
Ex: Ethelene diamine tetra acetic acid , Citric acid , Tartaric acid and some Amino acids acts as
Chelating agents.
13. Co-solvent :-
Improve solubility of poorly soluble compounds.
Prevent potential for hydrolysis.
14. Emulsifying Agents:- maintain stabilization.
Ex: Lecithin.
Polysorbate 80.
.
Problems associated with PARENTERLS
[A]: Syringeability:- Ease of withdrawal from vial to syringe.
Ability of the suspensions to pass easily through Hypodermic needle
on transfer from the prior to injections.
Characteristics of Suspensions:
 Ease of withdraw clogging and foaming tendencies & accuracy of dose measurements.
 If there is increase in the viscosity , density , particle size and concentration of solids in
suspension hinders the syringeability of suspension.
 A suitable test is to ensure that the entire suspension passes through a 25-gauge needle of
internal diameter about 0.260 – 0.3 mm.
Preparation & Stability of Large Volume Parenterals by PRINCE THAKUR
[B]: INJECTIBILITY:- It refers to the performance of suspension during injection and
includes factors such as pressure or force required for injection.
Tinius Olsen H10KS (Tinius Olsen Ltd. , Phennsylvania, USA)
Requirements:
 Evenness of flow , aspiration qualities and freedom from clogging.
 The syringeability and injectability of suspension are closely related to the Viscosity &
Particle charateristics of the suspension.
[C]: BLOCKAGE/CLOGGING:- of syringe needles while administrating a suspension may
occur because of a single large particles or an aggregate that blocks the Lumen of the needle or
because of a bridging effect of the particles.
 It is Advisable to Avoid Particles Greater than one third of the internal diameter of the needle
to prevent Clogging.
 Clogging , if observed at or near the needle end , is usually caused by restrictions to flow from the
suspension and may involve combination of factors such as Vehicle , wetting of particles , particle size ,
shape & distribution viscosity, and flow characteristics of the suspension.
[D]: DRAINAGE:- Drainage refers to the ability of the suspension to break cleanly away from
the inner walls of the primary Container-Closure system and is another characteristics , of a well
formulated characteristic of a Well Formulated Parentrals Suspension.
Silicone coating of container , vials , & plugs with dimethicone can improve the drainage of slightly
over flocculated systems as well as good suspensions.
[E]: RESUSPENDBILITY:-
 Resuspendibility describes the ability of the suspension to uniformly disperse
with minimal shaking after it has stood for some time.
 Qualitatively, light transmittance through the upper solution in a cylinder
after it has been spun for about 2 minutes at 75 rpm can be used to detect the
redispersion properties of the system.
 Resuspendiblity becomes a problem for suspension that forms cakes on
standing due to the deflocculated particles. Caking describes a process by
which which the particles undergo growth the fusion to form a non-dispersible
mass.
Preparation & Stability of Large Volume Parenterals by PRINCE THAKUR
Stability Studies for Large Volume Parenterals: 1. Effect of Temperature:-
Preparation & Stability of Large Volume Parenterals by PRINCE THAKUR
[2]. Water Loss:-
oo
[3]. STRESS TESTING:- Stress Testing is likely to be carried out a single Batch of drug
substance.
 It should include the Effect of Temperatures(in 10,50,60 degree Celsius, etc ) .
Humidity (75% RH or greater) where appropriate , oxidation , and photolysis on the drug
substance.
 The testing should also evaluate the susceptibility of the drug substance to hydrolysis across a
wide range of pH values when in solution or suspension.
 Photostability testing should be an integral part of Stress Testing. The standard conditions for
photostability testing are described in ICH Q1B.
 Examining degradation products under stress conditions is useful in establishing degradation
pathways and developing and validating suitable analytical procedures.
Results from these studies will form an integral part of the information provided to
Regulatory Authorities.
[4]. Product Packaging Interactions:- incompatibilities may result in the formation of
insoluble complexes while impurities from packaging container can initiate drug Degradative
Reactions.
 Selection of the desired packaging components aids in ensuring product- package
compatibility. Ex: PVC, Cyclic olefin Polymer, Ethylene vinyl acetate.
[5]. Compatibility with Diluents:- The choice of diluent(s) for the admixture compatibility
and stability studies should be made according to the requirements of the clinical program. However, any
gross incompatibilities observed in probe admixture studies may help eliminate those choices.
In certain cases, the preformulation experience may also help eliminate some of the choices.
For example, in the case of biologics, incompatibilities with sodium chloride may have been
observed in the preformulation studies in the form of one or more of the following: increase in
opalescence, particle formation, shaking stress instabilities, and/or soluble aggregate
formation.
In those cases, normal saline may not be the best choice for diluent.
Similarly, certain biologics may be prone to destabilization due to interaction with reducing
sugars, rendering them incompatible with diluents containing dextrose or glucose .In certain
cases the diluent may contain trace amounts of impurities.
TEST for Parenterals
1. Weight variation or content uniformity.
2. Particulate matter in injections.
3. Bacterial endotoxin test.
4. Pyrogen test.
5. Sterility test.
1. Weight variation or content uniformity test
This test is intended for sterile solids used for parenteral preparation.
The weight of 10 individual sterile units is noted and the content is removed from them and empty
individual sterile unit is weighed intern.
Then net weight is calculated by subtracting empty sterile unit weight form gross weight. The content of
active ingredient in each sterile unit is calculated by performing the assay according to the individual
monographs.
The content in 10 sterile units is calculated by performing the assay. The dose uniformity is met if the
amount of active ingredient is within the range of 85-115.0% of label claim as determine by the content
uniformity method or weight variation method.
2. Particulate matter in injections
The preparations intended for parenteral use should be free form particulate matter and should be clear
when inspected visually. Two methods are described by USP according to the filled volume of the product to
be tested.
 For large volume parenterals (LVP’s), a filtration followed by microscopical examination procedure is
used.
 For small volume parenterals (SVP’s)a light obscuration based sensor containing electronic liquid-borne
particle counter system is used.
3. Bacterial Endotoxin test
LAL (Limulus Amebocyte Lysate) test is used to characterize the bacterial endotoxin that may be present.
The LAL reagent is used for gel-clot formation.
The test is performed using stated amounts of volumes of products, standard, positive control, negative
control of endotoxin.
The tubes are incubated at 37+-1C FOR 60+-2 minutes .
When the tubes are inverted at 180 degree angle,
formation of firm gel confirms positive reaction.
While formation of a viscous gel that doesn’t maintain its integrity or absence of a firm gel confirms negative
reaction.
 The test is invalid if the negative control shows gel-clot end point.
4. Pyrogen test
 It is performed by using rabbits as test animals. Initially 10 ml/kg body weigh of animal is injected
through vein at 37+-2C within ten minutes from start of administration.
 The temperatures are recorded at 1, 2 and 3 hours after injection.
 The requirements of USP are met if the rise in temperature of individual rabbit is NMT 0.6C and the
sum of rise in temperature of three rabbits is NMT 1.4C.
 If any one rabbit shows a rise in temperature of 0.6C and sum of rise in temperature of three rabbits
exceeds 1.40C then the test is repeated using 5 rabbits.
 The requirements are met if 3 out of 8 rabbits shows an individual rise in temperature of NMT 0.6C and
sum of maximum rise in temperature of 8 rabbits is NMT 3.7C.
5. Sterility test
 Growth promotion medium and incubation conditions are selected based on the test microorganism.
 The sterility test is done using direct transfer and membrane filtration techniques.
 Membrane filtration technique is suitable for liquids, soluble powders with bacteria static or fungi
static properties, oils, creams and ointments.
 Sterility test by direct transfer is performed by aseptic transfer of specified volume from test
container to culture medium and incubated for 14 days and visual observation of medium is done on
3rd, 4th, 5th, 7th, 8th and 14th day.
 A membrane filter with porosity of 0.45um with diameter of 47mm with flow rate of 55-75 ml of
water per minute .
 The test meets the requirements when no growth is observed and if growth is observed then the test
is repeated in the second stage and generally second stage is repeated with double the number of
specimens tested in first stage when the test was found to be conducted under faulty or inadequate
aseptic techniques.
USP sterility tests growth promotion microorganisms
Medium Test microorganisms Incubation
Temperature (C) Conditions
Fluid thioglycollate Bacillus subtillis (ATCC No. 6633) 30 to 35 Aerobic
Candida albicans (ATCC No. 8482) 30 to 35
Bacteroides vulgatus (ATCC No. 8482) 30 to 35
Alternative thioglycollate Bacteroides vulgatus (ATCC No. 8482) 30 to 35 Anaerobic
Soybean-casein digest Bacillus subtillis (ATCC No. 6633) 20 to 25 Aerobic
Candida albicans (ATCC No. 10231 20 to 25
Preparation & Stability of Large Volume Parenterals by PRINCE THAKUR
THANK
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Preparation & Stability of Large Volume Parenterals by PRINCE THAKUR

  • 1. PREPRATION & STABILITY OF LARGE VOLUME PARENTERALS PRINCE THAKUR M Pharmacy {1st Year}
  • 2. CONTENTS A. Introduction. B. Types of Large Volume Parentrals. C. Preparation of Large Volume Parentrals. D. Problems associated with Parentrals. E. Stability Studies for Large Volume Parenterals
  • 3. INTRODUCTION Large volume parenterals solutions are employed in maintenance therapy for the patient entering or recovering from surgery and for the patient who is unconscious and unable to take Fluids, Electrolytes and nutrition orally. These solutions may also be used in replacement therapy for patients who have suffered a heavy loss of fluids and electrolytes. These are having range about 100 ml – 1 litre. These are delivered through IV-Route. These are supplied in single large dose containers.
  • 4. Maintenance Therapy When patient is receiving parenteral These are fluids for only a few days Simple solutions Providing adequate amounts of water, dextrose and small amounts of Sodium &. Potassium When patient are unable to take oral nutrition slightly for Longer Periods (3-6 days) High Caloric Content solution given. Like Carbohydrate , Protein, Fat.
  • 5. Administration: Large Volume Parenteral are slowly administered through a large vein such as Superior Vena Cava , which is Beneath the clavicle and near the heart.  About 10% dextrose solution given by superior vena cava. Function:-  This permits Rapid Dilution of the concentrated Hyperalimentation fluid and minimizes the risk of tissue or cellular damage due to Hypertonicity of the solution.
  • 6. TNAs(Three in one): Total Nutrient Admixture include all substrate necessary for nutritional support Carbohydrates , Protein , Fat & Electrolytes. In 1994(April) the FDA issued a safety alert regarding the hazards of precipitation associated with Parenteral Nutrition. 2 deaths Reported 2 other cases of Respiratory distress Because of TNAs(Formation of Calcium phosphate and deposition of its crystals in Lung Tissue).
  • 7. Calcium phosphate get precipitate in the admixture FDA approves that filter be used(0.22 micron meter) When infusing either central or peripheral parenterals nutrition admixtures Filter having both Bacterial retentive and air- elimininating filters have been recommended for use with Lipid Free(two-in-one) parenteral nutrient solutions  Three-in-one Lipid Emulsion causes problem it obscures any precipitate.  Thus, Two-in-one Lipid Emulsion are employed.
  • 8. TYPES OF LARGE VOLUME PARENTRALS : (A): Hyperalimentation Solution. (B): Cardioplegia Solution. (C): Peritoneal Dialysis Solution. (D): Irrigating Solutions. {1}: Hyperalimentation Solutions: It is a method of feeding patients by infusing a mixture of all necessary nutrients into the circulatory system, thus Bypassing the GI-Tract.  By these solutions, administrations of large amount of nutrients to patients who is unable to take food orally for several weeks at caloric intake levels of 4000 kcal/day or more.  Development of Subclavian vein cannulation- infused fluid is rapidly diluted by the high blood flow in the subclavian vein.  Commonly consist of mixtures of dextrose, amino acids & lipids, added electrolytes, trace metals & vitamins  Administration of life-saving or life-sustaining nutrients to comatose patients or to patients undergoing treatment for esophageal obstruction, GI diseases (including cancer), ulcer.
  • 10. FORMULATION: CONTENT SOURCES • Calories Dextrose • Nitrogen Crystalline amino acids • Electrolytes Na, K , Cl, PO4 • Vitamins Water soluble, Fat soluble • Elements Traces of Zn , Cu , Mn , Cr.
  • 11. {2}: Cardioplegic Solutions: Large Volume Parenterals are used in Heart Surgery to prevent injury to Myocardium during Reperfusion , as well as to maintain bloodless operating field.  Reperfusion or Reoxygenation injury, it is the tissue damage caused when blood supply returns to tissue after a period of lack of oxygen or ischemia.  Sometimes called, Ischemia- Reperfusion Injury(IRI).  It maintains the Diastolic arrest.  Its administration in cold form(in order to cool the Myocardium and Minimize activity).  Slightly Hypertonic & Alkaline to compensate metabolic acidosis and to minimize reperfusion injury resulting from tissue edema.
  • 13. {3}: Peritoneal Dialysis Solution:  Are infused continuously into the abdominal cavity, bathing the peritonium & are then continuously withdrawn.  To remove the toxic substances from the body or to aid & accelerate the excretion function normal to the kidneys.  The process is employed to counteract some forms of drug or chemical toxicity as well as to treat acute renal insufficiency.  Solution contain glucose & have an ionic content similar to normal extracellular fluid. An antibiotic is often added to these solution as a prophylactic measure. Cleansing fluid Tube inserted Inside Abdominal Dialysate absorb waste product (Dialysate) (Catheter) Cavity from Blood vessels in abdominal lining Discarded then
  • 15. {4}: Irrigating Solutions:  Are intended to irrigate, flush, & aid in cleansing body cavities & wounds.  Although certain IV solutions, such as normal saline, may be used as irrigating solutions should not be used parenterally.(Because they enter in systemic circulation in relatively in large volume).  The Risk of dilutional states is inversely proportional to electrolyte concentrations of administered Parenteral solutions.  They must be sterile, pyrogen-free, & made & handled with the same care as parenteral solutions.  Also used in treatment of serious wounds infused into the Blood stream.
  • 17. PREPARATION OF LARGE VOLUME PARENTRELS: [1]. Therapeutic Agents:- Antibiotics, Anticancer, Steroids, Vaccines, Antipyretic, Analgesics, Anti-inflammatory & to know about the physical & chemical properties of the drug molecule.  LVP like Dextrose, NaCl, or combination etc.
  • 18. [2]. Aqueous Vehicle:- According to USP , Water for Injection used which is highly sterilized.  According to USP, it include not more than 10 parts per million of total solids(mg/L). pH (5.0- 7.0).  Water for Injection is generally prepared by either Distillation or Reverse Osmosis.
  • 19. Compression still: for production of LVP with Low consumption of energy on water. Produce water 5- 10 times more cost effectively then Multiple effect distillers. PROCEDURE:- Boiling by heating elements turned ON As the water reaches near boiling temperatures The Compressor Turns ON Steam is pressurized which raises the steam temperature The pressurized steam gives off its heat to the Tap Water inside the boiling chamber Causing water to boil Steam will be condensed Which creates more steam this gives Latent heat HOT WATER produces(slightly cooler than boiling temperature) One of the heating elements will cycle ON and OFF as per periodically need.
  • 20. 3. Sterile Water for Injection:-  Single dose containers .  It is hypotonic , non-pyrogenic , sterile made by distillation .  It contains no anti-microbial or bacteriostatic , additives or buffer.  pH- (5.5-7.0).  Not for IM , IV use because Hemolysis.  It is used for washing wounds , surgical incisions or body tissues.
  • 21. 5. Water Miscible Vehicles:-  As the name suggest , this occupies some part of the vehicle and it helps in decresing hydrolysis and to solubilize some drugs. Ex: Ethyl alcohol, Propylene glycol. 6. Non-Aqueous Vehicle:- Ex: Fixed oils, peanut oils, corn oils , cotton seed oils , Sesame oils.
  • 22. 7. Anti-oxidants:- Protects formulation from oxidation & maintain the product stability. Ex: (a) Reducing Agents: a substance that reduces a chemical compound usually by donating electrons. E.g ; Ascorbic Acid, Thiourea. (b) Blocking Agents: Tocopherol.
  • 23. 8. Surfactants:- Help to solublise the active ingredient. • Polyoxythylene sorbitan mono-oleate. • Sorbitan mono-oleate. 9. Tonicity Agents:- Formulation needs to be isotonic to avoid destruction of RBCs, Irritation, and tissue damage. More important for Large volumes , Rapidly administered and extra-vascular injections. Reduces the pain on injection. Ex: Sorbitan mono-oleate ,NaCl , KCl ,Dextrose solution.
  • 24. 10. Other Additives:- Buffers: To stabilize the emulsion from chemical degradation. To maintain the pH. Ex: Citrate , Acetate , phosphate. Bulking Agents: for freeze dried preparations(solids). Ex: Mannitol, Lactose , Sucrose , Dextran.
  • 25. 12. Chelating Agents :- Also used in Limited number. Improve efficacy of Anti-oxidants. To remove traces Elements that catalyse oxidative degeneration. Ex: Ethelene diamine tetra acetic acid , Citric acid , Tartaric acid and some Amino acids acts as Chelating agents. 13. Co-solvent :- Improve solubility of poorly soluble compounds. Prevent potential for hydrolysis.
  • 26. 14. Emulsifying Agents:- maintain stabilization. Ex: Lecithin. Polysorbate 80. .
  • 27. Problems associated with PARENTERLS [A]: Syringeability:- Ease of withdrawal from vial to syringe. Ability of the suspensions to pass easily through Hypodermic needle on transfer from the prior to injections. Characteristics of Suspensions:  Ease of withdraw clogging and foaming tendencies & accuracy of dose measurements.  If there is increase in the viscosity , density , particle size and concentration of solids in suspension hinders the syringeability of suspension.  A suitable test is to ensure that the entire suspension passes through a 25-gauge needle of internal diameter about 0.260 – 0.3 mm.
  • 29. [B]: INJECTIBILITY:- It refers to the performance of suspension during injection and includes factors such as pressure or force required for injection. Tinius Olsen H10KS (Tinius Olsen Ltd. , Phennsylvania, USA)
  • 30. Requirements:  Evenness of flow , aspiration qualities and freedom from clogging.  The syringeability and injectability of suspension are closely related to the Viscosity & Particle charateristics of the suspension.
  • 31. [C]: BLOCKAGE/CLOGGING:- of syringe needles while administrating a suspension may occur because of a single large particles or an aggregate that blocks the Lumen of the needle or because of a bridging effect of the particles.
  • 32.  It is Advisable to Avoid Particles Greater than one third of the internal diameter of the needle to prevent Clogging.  Clogging , if observed at or near the needle end , is usually caused by restrictions to flow from the suspension and may involve combination of factors such as Vehicle , wetting of particles , particle size , shape & distribution viscosity, and flow characteristics of the suspension.
  • 33. [D]: DRAINAGE:- Drainage refers to the ability of the suspension to break cleanly away from the inner walls of the primary Container-Closure system and is another characteristics , of a well formulated characteristic of a Well Formulated Parentrals Suspension. Silicone coating of container , vials , & plugs with dimethicone can improve the drainage of slightly over flocculated systems as well as good suspensions.
  • 34. [E]: RESUSPENDBILITY:-  Resuspendibility describes the ability of the suspension to uniformly disperse with minimal shaking after it has stood for some time.  Qualitatively, light transmittance through the upper solution in a cylinder after it has been spun for about 2 minutes at 75 rpm can be used to detect the redispersion properties of the system.  Resuspendiblity becomes a problem for suspension that forms cakes on standing due to the deflocculated particles. Caking describes a process by which which the particles undergo growth the fusion to form a non-dispersible mass.
  • 36. Stability Studies for Large Volume Parenterals: 1. Effect of Temperature:-
  • 39. [3]. STRESS TESTING:- Stress Testing is likely to be carried out a single Batch of drug substance.  It should include the Effect of Temperatures(in 10,50,60 degree Celsius, etc ) . Humidity (75% RH or greater) where appropriate , oxidation , and photolysis on the drug substance.  The testing should also evaluate the susceptibility of the drug substance to hydrolysis across a wide range of pH values when in solution or suspension.  Photostability testing should be an integral part of Stress Testing. The standard conditions for photostability testing are described in ICH Q1B.  Examining degradation products under stress conditions is useful in establishing degradation pathways and developing and validating suitable analytical procedures. Results from these studies will form an integral part of the information provided to Regulatory Authorities.
  • 40. [4]. Product Packaging Interactions:- incompatibilities may result in the formation of insoluble complexes while impurities from packaging container can initiate drug Degradative Reactions.  Selection of the desired packaging components aids in ensuring product- package compatibility. Ex: PVC, Cyclic olefin Polymer, Ethylene vinyl acetate. [5]. Compatibility with Diluents:- The choice of diluent(s) for the admixture compatibility and stability studies should be made according to the requirements of the clinical program. However, any gross incompatibilities observed in probe admixture studies may help eliminate those choices. In certain cases, the preformulation experience may also help eliminate some of the choices. For example, in the case of biologics, incompatibilities with sodium chloride may have been observed in the preformulation studies in the form of one or more of the following: increase in opalescence, particle formation, shaking stress instabilities, and/or soluble aggregate formation. In those cases, normal saline may not be the best choice for diluent. Similarly, certain biologics may be prone to destabilization due to interaction with reducing sugars, rendering them incompatible with diluents containing dextrose or glucose .In certain cases the diluent may contain trace amounts of impurities.
  • 41. TEST for Parenterals 1. Weight variation or content uniformity. 2. Particulate matter in injections. 3. Bacterial endotoxin test. 4. Pyrogen test. 5. Sterility test. 1. Weight variation or content uniformity test This test is intended for sterile solids used for parenteral preparation. The weight of 10 individual sterile units is noted and the content is removed from them and empty individual sterile unit is weighed intern. Then net weight is calculated by subtracting empty sterile unit weight form gross weight. The content of active ingredient in each sterile unit is calculated by performing the assay according to the individual monographs. The content in 10 sterile units is calculated by performing the assay. The dose uniformity is met if the amount of active ingredient is within the range of 85-115.0% of label claim as determine by the content uniformity method or weight variation method.
  • 42. 2. Particulate matter in injections The preparations intended for parenteral use should be free form particulate matter and should be clear when inspected visually. Two methods are described by USP according to the filled volume of the product to be tested.  For large volume parenterals (LVP’s), a filtration followed by microscopical examination procedure is used.  For small volume parenterals (SVP’s)a light obscuration based sensor containing electronic liquid-borne particle counter system is used.
  • 43. 3. Bacterial Endotoxin test LAL (Limulus Amebocyte Lysate) test is used to characterize the bacterial endotoxin that may be present. The LAL reagent is used for gel-clot formation. The test is performed using stated amounts of volumes of products, standard, positive control, negative control of endotoxin. The tubes are incubated at 37+-1C FOR 60+-2 minutes . When the tubes are inverted at 180 degree angle, formation of firm gel confirms positive reaction. While formation of a viscous gel that doesn’t maintain its integrity or absence of a firm gel confirms negative reaction.  The test is invalid if the negative control shows gel-clot end point.
  • 44. 4. Pyrogen test  It is performed by using rabbits as test animals. Initially 10 ml/kg body weigh of animal is injected through vein at 37+-2C within ten minutes from start of administration.  The temperatures are recorded at 1, 2 and 3 hours after injection.  The requirements of USP are met if the rise in temperature of individual rabbit is NMT 0.6C and the sum of rise in temperature of three rabbits is NMT 1.4C.  If any one rabbit shows a rise in temperature of 0.6C and sum of rise in temperature of three rabbits exceeds 1.40C then the test is repeated using 5 rabbits.  The requirements are met if 3 out of 8 rabbits shows an individual rise in temperature of NMT 0.6C and sum of maximum rise in temperature of 8 rabbits is NMT 3.7C.
  • 45. 5. Sterility test  Growth promotion medium and incubation conditions are selected based on the test microorganism.  The sterility test is done using direct transfer and membrane filtration techniques.  Membrane filtration technique is suitable for liquids, soluble powders with bacteria static or fungi static properties, oils, creams and ointments.  Sterility test by direct transfer is performed by aseptic transfer of specified volume from test container to culture medium and incubated for 14 days and visual observation of medium is done on 3rd, 4th, 5th, 7th, 8th and 14th day.  A membrane filter with porosity of 0.45um with diameter of 47mm with flow rate of 55-75 ml of water per minute .  The test meets the requirements when no growth is observed and if growth is observed then the test is repeated in the second stage and generally second stage is repeated with double the number of specimens tested in first stage when the test was found to be conducted under faulty or inadequate aseptic techniques.
  • 46. USP sterility tests growth promotion microorganisms Medium Test microorganisms Incubation Temperature (C) Conditions Fluid thioglycollate Bacillus subtillis (ATCC No. 6633) 30 to 35 Aerobic Candida albicans (ATCC No. 8482) 30 to 35 Bacteroides vulgatus (ATCC No. 8482) 30 to 35 Alternative thioglycollate Bacteroides vulgatus (ATCC No. 8482) 30 to 35 Anaerobic Soybean-casein digest Bacillus subtillis (ATCC No. 6633) 20 to 25 Aerobic Candida albicans (ATCC No. 10231 20 to 25