PARENTERAL DRUG DELIVERY

PARENTERAL DRUG DELIVERY
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enteron: intestine (i.e. beside the intestine)
PARENTERALS para: outside enteron: intestine (i.e. beside the intestine) These are the preparations which are given other than oral routes. Injections: These are Sterile, Pyrogen free preparations intended to be administered parenterally (outside alimentary tract). STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Why Parenteral? Parenteral Route Is Used bcoz 1) Rapid action 2) Oral route can not be used 3) Not effective except as injection 4) Many new drugs particularly those derived from new development in biotechnologically can only be given by parenteral coz they are inactivated in GIT if given orally. 5) New drugs require to maintain potency & specificity sodium that they are given by parenteral. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Advantages: Quick onset of action
Suitable for the drugs which are not administered by oral route Useful for unconscious or vomiting patients. Duration of action can be prolonged by modifying formulation. Suitable for nutritive like glucose & electrolyte. Suitable for the drugs which are inactivated in GIT or HCl (GI fluid) STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Disadvantages: Once injected cannot be controlled (retreat)
Injections may cause pain at the site of injection Only trained person is required If given by wrong route, difficult to control adverse effect Difficult to save patient if overdose Sensitivity or allergic reaction at the site of injection Requires strict control of sterility & non pyrogenicity than other formulation. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Necessities of Parenteral preparations:
Sterility (must) Free from Pyrogen (must) Free from particulate matter (must) Clarity (must) Stability (must) Isotonicity (should) Solvents or vehicles used must meet special purity and other standards. Restrictions on buffers, stabilizers, antimicrobial preservative. Do not use coloring agents. Must be prepared under aseptic conditions. Specific and high quality packaging. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Routes of Parenteral Administration
Subcutaneous (21) Intravenous (21) Intramuscular (20) Intradermal (23) Intra arterial (20-22) Epidermis Dermis Vein Subcutaneous tissue Artery STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala Muscle

Parental Routes of Administration:
Most Common: 1. Subcutaneous (SC; SQ ;Sub Q) 2. Intramuscular (IM) 3. Intravenous (IV) Others: Intra-arterial (IA) 5. Intrathecal 6. Intraarticular 7. Intrapleural 8. Intracardial 9. Intradermal (Diagnostic) STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Intravenous Route (IV)
STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Intravenous (IV): Given: Into the vein 1 to 1000 ml
1 inch ,19 to 20 gauge needle with injection rate 1ml/ 10 sec. for volume upto 5 ml & 1 ml/ 20 sec. for volume more than 5 ml. Given: Aqueous solutions Hydro alcoholic solutions Emulsions Liposome STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

IV infusion of large volume fluids ( ml) has become increasingly popular. This technique is called as Venoclysis. This is used to supply electrolytes & nutrients to restore blood volume & to prevent tissue dehydration. Combination of parenteral dosage forms for administration as a unit product is known as an IV admixture. Lactated Ringer Injection USP NaCl Injection USP (0.9 %)– (replenish fluid & electrolyte) Dextrose Injection USP (fluid & electrolyte) STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Advantage: May be a life-saving procedure because of the placement of the drug directly into the circulation and the prompt actions which ensues. Disadvantage: Once the drug administered, it cannot be retrieved. In the case of adverse reaction to the drug, for instance, the drug cannot be easily removed from the circulation. Precautions: Strict aseptic precautions must be taken at all times to avoid risk of infection. The syringes and needles used must be sterilized and to the point of entrance must be disinfected to reduce chance of carrying bacteria from the skin into the blood via the needle STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

NOTE: Not only are the injectable solutions sterile, syringes, needles must also be disinfected to reduce the chance of carrying bacteria A backflow of blood into the administration set or syringe indicates proper placement of the needle in the vein Intravenous drugs ordinarily must be aqueous solution; they must mix with the circulating blood and not precipitate from solution. Such an event can lead to pulmonary micropillary occlusion and blockage of blood flow. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Hazard Of Intravenous Injection
Intravenous Route (IV) Hazard Of Intravenous Injection The possibility of thrombus formation induced by the touching of the wall of the vein by the catheter or needle. Thrombus is a blood clot formed within the blood vessel (or heart) due usually to a slowing of the circulation or to an alteration of the blood or vessel wall. Once such a blot circulates, it becomes an Embolus carried by the blood stream until it lodges in a blood vessel, obstructing it, and resulting in blockage or occlusion referred to as an Embolism. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Intramuscular (IM): Striated muscle fibre
0.5 to 2 ml sometimes upto 4 ml 1 to 1.5 inch & 19 to 22 gauge needle is used Preferably isotonic Principle sites: Gluteal (buttocks) Deltoid (upper arms) Vastus lateralis (lateral thigh) Given: Solutions Emulsions Oils Suspension STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Intramuscular (IM) STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Intramuscular (IM) Intramuscular injections of drugs provide effects that are less rapid, but generally of greater duration than those obtained from intravenous administration IM are performed deep into the skeletal muscles. The point of injection should be as far as possible from major nerves and blood vessels. Injuries to patients from IM injection usually are related to the point at which the needle entered and where the medication was deposited. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Intramuscular (IM) 1. Paralysis resulting from neural damage
Such injuries include: 1. Paralysis resulting from neural damage 2. Abscesses 3. Cysts 4. Embolism 5. Hematoma 6. Sloughing of the skin 7. Scar formation Adult – upper outer quadrant of the gluteus maximus Infants – gluteal area is small, composed primarily fats not muscle, so not recommended Infants and Young children – deltoid, muscles of the upper arm or the midlateral muscles of the thigh STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Intramuscular (IM) Volume of Administration: limited :
5 mL in the gluteal region 2 mL in the deltoid of the arm. Injection is 2 to 3 inches deep 20 to 22 gauge needle. To avoid staining: it must be injected only into the muscle mass of the upper outer quadrant of the buttock. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Intramuscular (IM) The skin is displaced laterally, then needle inserted and syringe aspirated, and injection performed slowly and smoothly. The needle is then withdrawn and the skin release. This create a “Z” pattern that blocks infiltration of medication into subcutaneous tissue. The Z-Track Injection techniques is useful for IM injections of medications that stain upper tissue. Examples: Iron dextran injection –irritate tissues Diazepam (Valium) – by sealing in the lower muscle STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Subcutaneous (SC; SQ ;Sub Q):
The injection is given under the skin Need to be isotonic Upto 2 ml is given Using ½ to 1 inch 23 gauge needle or smaller needle Given: Vaccines Insulin Scopolamine Epinephrine STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Subcutaneous Route (SC)
May be utilized for the injection of small amounts of medication or of drugs beneath the surface of the skin of the upper arm, the anterior surface of the thigh, and the lower portion of the abdomen. The site of injection is usually rotated when injections are frequently given, as with daily insulin injection. The maximum amount of drug given SC is about mL Amounts greater than 2 mL will most likely cause painful pressure. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Subcutaneous Route (SC)
Syringes: up to 3 mL capacities Utilizing needles: 24 to 26 gauges SC insulin needles: gauge between 25 to 30 needle length between 5-16 to 5-8 inch. Upon insertion, if blood appears in the syringe, a new site should be selected. Irritating drugs and those in thick suspension may produce induration, sloughing, or abscess and may be painful. Such preparations are not suitable for subcutaneous injection STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Intraarticular: Given: Given directly into the joints 2 to 20 ml
5 inch 22 gauge Must be isotonic Given: Morphine LA Steroids NSAID’s Antibiotics STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Intrapleural: Given: Given directly into the pleural cavity or lung
Used for fluid withdrawal 2 to 30 ml 2 to 5 inch, 16 to 22 gauge needle Given: LA Narcotics Chemotherapeutic agents STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Intracardial: Given: Directly given into the heart 0.2 to 1 ml
5 inch , 22 gauge needle Given: Cadiotonics Calcium salts as a calcium channel blockers STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Intradermal: Given: Also called as diagnostic testing 0.05 ml
½ inch, 25 to 26 gauge needle Should be isotonic Given: Diagnostic agents STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Intrathecal: Given: Also called intra-spinal
Directly given into the spinal cord 1 to 4 ml 24 to 28 gauge Must be isotonic Given: LA Analgesics Neuroleptics STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Intra-arterial (IA): Given: Direct into the artery 2 to 20 ml
20 to 22 gauge Solutions & emulsions can be administered Given: Radio opaque media Antineoplastic Antibiotics STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

The inaction are given directly in to the artery
Intra-arterial injection Intracardiac injection Intrathecal injection These are given into the subachonoid space the surround the spinal cord. This route is used for spinal anesthesia. The inaction are given directly in to the artery These are given into the heart muscle or ventricle at the time of emergency only. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Intracisternal injection
These are given in b/w first & second cervical nerve. Used for CSF for diagnostic purpose. Peridural injection These are given in b/w the dura matter & inner aspect of vertebra. Used for given spinal anesthesia. Intra- articular injection These are given in into the articulating ends of bones in a joint. Used for lubricating the joints. Intracerebral injection These are given into the cerebrum. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

STERILITY TESTING FOR PARENTERAL PRODUCTS

1. Sterility testing - definition
Sterility testing attempts to reveal the presence or absence of viable micro-organisms in a sample number of containers taken from batch of product. Based on results obtained from testing the sample a decision is made as to the sterility of the batch. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

1.2.3.Culture media for sterility testing
capable of initiating and maintaining the vigorous growth of a small number of organisms sterile Types of media: Fluid thioglycollate medium Soya-bean casein digest medium other media STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

1.2.3.1.Fluid thioglycollate medium
composition described in next slide. specific role of some ingredients primarily intended for the culture of anaerobic bacteria incubation of the media: 14 days at °C STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Fluid thioglycollate medium

1.2.3.2.Soya-bean casein digest medium
primarily intended for the culture of both fungi and aerobic bacteria specific role of some ingredients incubation of the media: 14 days at °C STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Soya-bean casein digest medium

1.3.The test method for sterility of the product
Membrane filtration Direct inoculation of the culture medium STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

1.3.1. Membrane filtration Appropriate for : (advantage)
filterable aqueous preparations alcoholic preparations oily preparations preparations miscible with or soluble in aqueous or oily (solvents with no antimicrobial effect) solutions to be examined must be introduced and filtered under aseptic conditions All steps of this procedure are performed aseptically in a Class 100 Laminar Flow Hood STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

1.3.1.1.Selection of filters for membrane filtration
pore size of 0.45 m effectiveness established in the retention of micro-organisms appropriate composition the size of filter discs is about 50 mm in diameter STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Scheme for sterility test by direct inoculation
Scheme for sterility test by membrane filtration Scheme for sterility test by direct inoculation STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Advantages of the filtration method
wide applications a large volume can be tested with one filter smaller volume of culture media is required applicable to substances for which no satisfactory inactivators are known neutralization is possible on the filter subculturing is often eliminated shorter time of incubation compared with direct inoculation STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Minimum number of items to be tested

PYROGENS AND PYROGEN TESTING

I Love The Rabbit! STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Pyrogens Pyrogenic - means producing fever
Pyrogens - fever inducing substances Having nature Endogenous (inside body) Exogenous (outside body) Exogenous pyrogens – mainly lipopolysaccharides bacterial origin, but not necessary STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Structure of endotoxins
Produced mostly by gram-negative bacteria Endotoxin - complex of pyrogenic lipopolysaccharide, lipid part of the lipopolysaccharide is the main pyrogenic agent; polysaccharide part increases solubility STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Sources of pyrogen contamination
solvent - possibly the most important source the medicament the apparatus the method of storage between preparation and sterilization STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

The endotoxin characteristics
thermostable water-soluble unaffected by the common bactericides non-volatile These are the reasons why pyrogens are difficult to destroy once produced in a product STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Tests for pyrogenic activity
Test for pyrogens = Rabbit test Bacterial endotoxins STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Test for pyrogens = Rabbit test
the development of the test for pyrogens reach in 1920 a pyrogen test was introduced into the USP XII (1942) The test consists of measuring the rise in body temperature in healthy rabbits by the intravenous injection of a sterile solution of the substance under the test. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Why the Rabbit? Reproducible pyrogenic response
Other species not predictable Similar threshold pyrogenic response to humans Monkeys, horses, dogs, cats, and rabbit have reproducible responses Rats, guinea pigs, mice, hamsters, chicks, etc, are irregular and unpredictable Rabbit and dog chosen chosen for economic purposes, BUT… Rabbit has labile thermoregulatory process, and is susceptible to false positives. A negative test is more significant than a positive one. The dog has a more stable thermoregulatory system, and is less sensitive to pyrogen. Therefore a positive is more significant than a negative one. Similar threshold pyrogenic response to humans. HOWEVER, as dose is increased, humans respond more vigorously. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Rabbit test - selection of animals (healthy, adult, not less than 1,5 kg,…) housing of animals (environmental problems: presence of strangers (unknown place), noise, T, …) equipment and material used in test (glassware, syringes, needles) retaining boxes (comfortable for rabbits as possible) thermometers (standardized position in rectum, precision of 0.1°C) STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Rabbit test Preliminary test (Sham Test)
intravenous injection of sterile pyrogen-free saline solution to exclude any animal showing an unusual response to the trauma (shock) of injection any animal showing a temperature variation greater than 0.6C is not used in the main test STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Rabbit test - main test: group of 3 rabbits
preparation and injection of the product: warming the product dissolving or dilution duration of injection: not more than 4 min the injected volume: not less than 0.5 ml per 1 kg and not more than 10 ml per kg of body mass determination of the initial and maximum temperature all rabbits should have initial T: from 38.0 to 39.8C the differences in initial T should not differ from one another by more than 1C STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

The result of pyrogen test:
No.of Rabbits Individual Tempt. rise (°c) Tempt. Rise in group (°c) Test 3 rabbits 0.6 1.4 Passes If above not passes 3+5 = 8 rabbits 3.7 If above test not passes perform the test again If above test not passes, the sample is said to be pyrogenic or go thr’ the sources of contamination of pyrogen. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Bacterial endotoxins to detect or quantify endotoxins of gram-negative bacterial origin reagent: amoebocyte lysate from horseshoe crab (Limulus polyphemus or Tachypleus tridentatus). The name of the test is also Limulus amebocyte lysate (LAL) test STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Limulus polyphemus = horseshoe crab

Mechanism of LAL enzymes located with the crab's amebocyte blood cells
the test is based on the primitive blood-clotting mechanism of the horseshoe crab enzymes located with the crab's amebocyte blood cells endotoxins initiation of an enzymatic coagulation cascade proteinaceous gel STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Test performance (short)
avoid endotoxin contamination Before the test: interfering factors should not be present equipment should be depyrogenated the sensitivity of the lysate should be known Test: equal V of LAL reagent and test solution (usually 0.1 ml of each) are mixed in a depyrogenated test-tube incubation at 37°C, 1 hour remove the tube - invert in one smooth motion (180°) - read (observe) the result pass-fail test STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

LAL test Three different techniques:
the gel-clot technique - gel formation the turbidimetric technique - the development of turbidity after cleavage of an endogenous substrate the chromogenic technique - the development of color after cleavage of a synthetic peptide-chromogen complex STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Advantages of LAL test Fast - 60 minutes vs. 180 minutes
Greater Sensitivity Less Variability Much Less False Positives Much Less Expensive Alternative to Animal Model cheaper, more accurate than other is performed in the pharmaceutical laboratory specific for endotoxins of gram-negative origin STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Particulate Matter Monitoring

Definition: Unwanted mobile insoluble matter other than gas bubbles present in the given product. It may be dangerous when the particle size is larger than R.B.C. & may block the blood vessel. This type of products are immediately rejected from the batch. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

The limit test for particulate matter is prescribed in I. P
The limit test for particulate matter is prescribed in I.P (A- 125) Applicable for: 100 ml or more volume containers of single dose LV given by IV infusion Not applicable for: Multidose injections Single dose SVP Injectable solutions constituted from sterile solids STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Permitted limits of particulate matter
Particle size in micrometer Max.No.of particles (equal to or larger than) per ml 50 Nil STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Sources of particulate matter
Contamination Contaminant Intrinsic contamination: Originally present in products e.g. Barium ions may react or leach with Sulphur ion which are already present in formulation may produce barium sulphate crystals. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Extrinsic contamination:
Material comes from outside or environment e.g. coming off the material from body & cloths of person Entry of particle from ceiling , walls & furniture May be in the form of cotton, glass rubber, plastics, tissues, insect fragments, bacterial contamination, dust, papers etc… STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Methods of monitoring particulate matter contamination
Visual method Coulter counter method Filtration method Light blockage method STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Coulter counter method:
Visual method: Simple method Filled container are examined against strong illuminated screen by holding neck & rotating it slowly or inverted it to keep out the foreign matter. Coulter counter method: It is used for detection of particles less than 0.1 micrometer in diameter. Based on electrode resistance. Sample is evaluated between two electrode & if particle found the resistance of electrode is increased. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Light blockage method:
Filtration method: It is used for counting the particles in hydraulic fluids. Sample passed thr’ filter Material is collected on filter Evaluated under microscope. Disadvantage: Skilled & trained person is required Light blockage method: Used for hydraulic oils Allows stream of fluid under test to pass between a bright white light source & photoiodide sensor. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Identification of Particulate Matter
Microscopy X- ray powder diffraction Mass microscopy Microchemical tests Electron microscopy etc… STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Significance of Particulate Matter monitoring
Its presence may causes: Septicemia Fever & blockage of blood vessels Quality of product may affect STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

TONICITY

Solution Solute Solvent Osmosis
A liquid (usually water) and its dissolved solutes Solute A substance that is dissolved in a liquid Solvent A liquid that has dissolved (or can dissolve) one or more solutes Osmosis The diffusion of water across a membrane. In osmosis, water diffuses from regions of higher water concentration to regions of lower water concentration. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

osmosis Osmosis is the diffusion of solvent through a semi- permeable membrane. Water always flows from lower solute concentration [dilute solution] to higher solute concentration until a balance is produced Osmotic pressure is the force that cause this diffusion . Tonicity is a measure of the osmotic pressure of two solutions separated by a semi-permeable membrane. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Types of Tonicity Hypertonic isotonic Hypotonic NaCl 2% NaCl 0.9%
solute ‹ solute Inside outside solute =solute solute › solute shrinkage equilibrium swelling STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

cytosol central vacuole
Tonicity and plant cells cytosol central vacuole When water is plentiful, it fills the central vacuole, pushes the cytosol against the cell wall, and helps maintain the cell's shape. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

cell wall plasma membrane
Tonicity and plant cells cell wall plasma membrane Plants wilt when water is scarce. They also wilt if salt is added to the soil. Why? When water is scarce, the central vacuole shrinks and the cell wall is unsupported. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Tonicity If the the fluid around the cell contains less dissolved solute than the fluid in the cell... ...the fluid is hypotonic compared with the cell. More water enters the cell than leaves. The cell may swell to the point of bursting. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Tonicity If the contents of a cell and the fluid around the cell have the same concentration of dissolved solutes... ...the fluid is isotonic compared with the cell. Water moves in and out in equal amounts. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Tonicity If the fluid around the cell contains more dissolved solute than the fluid inside the cell... ...the fluid is hypertonic compared with the cell. More water leaves the cell than enters. The cell shrinks. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

(a) Isotonic solution (b) Hypertonic solution (c) Hypotonic solution
What is the tonicity of the solutions that these red blood cells have been dropped into? W O R K T G E H (a) Isotonic solution (b) Hypertonic solution (c) Hypotonic solution Equal movement of water into and out of cells. Net water movement out of cells. Net water movement into cells. STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Why using isotonic solutions?

Isotonicity & route of administration
Subcutaneous injection: not necessarily “small dose” but isotonicity reduce pain. Hypodermoclysis should be isotonic “Large volume” Intramuscular injection should be isotonic or slightly hypertonic to increase penetration Intravenous injection should be isotonic “Large volume ” Hypotonic cause haemolysis Hypertonic solution may be administered slowly into a vein Hypertonic large volume administered through a cannula into large vessels. subcutaneous infusion, is the subcutaneous administration of fluids to the body. This would often be in the form of a saline or glucose solution STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Isotonicity & route of administration cont.
Intrathecal injestion Should be isotonic Eye drops Rapid diluted by tear, but most of it is isotonic to decrease irritation Eye lotions Preferably isotonic Nasal drops Isotonic, but not essentially STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Classes of adjustment of isotonicity
Class I Adding substace to lower f.p of solution to -0.52º Freezing point depression (FPD) “cryoscopic method”. NaCL equivalent method. Class II Adding H2O White –Vincent method STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

1- Freezing point depression (FPD) “cryoscopic method”.
F.P. of blood & tears = º Any solution have F.P. = º is isotonic. Any solution have F.P. › º is hypotonic - 0.4º hypotonic -0.6º hypertonic Add solute to hypotonic solution to reach f.p.d of blood (- 0.52º ) STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

How to calculate? = conc. gm/100 ml of adjusting substance
= f.p.d of 1% of unadjusted substance(table) X percentage strength = f.p.d of 1% of adjusting substance (table) STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Example I How much NaCl is required to render 100 ml of a 1% soln. of apomorphin HCL isotonic? F.p.d of 1%NaCl=0.58º, F.p.d of 1%drug=0.08º 1% drug º (0.52º- 0.08º=0.44º) 1% NaCl º w% NaCl º STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Example II adjust isotonicity of procaine HCl 3% using NaCl ? Fpd of 1%NaCl=0.57º, f.p.d of 1% drug=0.112º STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Preformulation Pharmaceutical and analytical investigation
Supports formulation development efforts for all dosage form Physicochemical properties of drug and combination with excipients, solvents and packaging components Studies carried out under stressed condition (oxygen, light, temp,humidity etc. ) PHYSICOCHEMCIAL PROPERTIES DRUG-EXCIPIENTS COMPATIBILITY STUDIES ACCELERATED STABILITY STUDIES STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Particle size, shape and crystallinity –polarizing microscope, electron microscope and optical microscope Melting point-change in melting point and changes during melting( colour, gas etc. ) Hygroscopicity- weighed sample in various humidity condition for 2 weeks (weight gain/loss)-determine storage condition STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Absorption spectra- unsaturation (UV-Visible –IR Spectra)-quantitative and qualitative
Optical Activity-biologically active form is selected (l-epinephrine active as vasoconstrictor ) Ionization constant –pH dependant solubility –potentiomentric titration STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Accelerated stability studies
Light Heat pH Oxygen Autoclaving STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

Drug –excipients compatibility
Placket –burman Factorial design STES, Sinhgad Institute of Pharmaceutical Sciences,Lonavala

PARENTERAL DRUG DELIVERY

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PARENTERAL DRUG DELIVERY

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