Modern pharmaceutics

Presented by
Bashant Kumar Sah
M pharm pharmaceutics department
,Nargund college of pharmacy
 Preformation Concepts
THE CONCEPT OF PREFORMULATION:-

Almost all drugs are marketed as tablets, capsules or both. Prior to the development of
these major dosage forms, it is essential that certain fundamental, physical and
chemical properties of the drug molecule and other properties of the drug powder are
determined. This information decides many of the subsequent events and approaches
in formulation development.
This first learning phase is known as preformulation

Definition:-

It can be defined as an investigation of physical and chemical properties of a drug

substance - alone and or when combined with excipients.

The overall objective of preformulation testing is to generate information useful to the

formulator in developing stable and safe dosage forms with good bioavailability.
During the early development of a new drug substance, the synthetic
chemist, alone or in cooperation with specialists in other disciplines
(including preformulation), may record some data which can be
appropriately considered as preformulation data.

This early data collection may include such information as

- Gross particle size,

- Melting point,

- Infrared analysis,

- Thin-layer chromatographic purity,

- And other characteristics .

These data are useful in guiding, and becoming part of, the main body
of preformulation work.
 Drug Excipient interactions -
different methods
 drugs excipients interaction is also called incompatibility and hence
 An incompatibility may be defined as…..
 “An undesirable drug interaction with one or more components of a formulation, resulting in changes in physical,
chemical, microbiological or therapeutic properties of the dosage form.”
 An incompatibility in dosage form can result in any of the following changes:
 change in colour/appearance;
 loss in mechanical properties (e.g., tablet hardness)
 changes to dissolution performance;
 physical form conversion;
 loss through sublimation;
 a decrease in potency; and
 increase in degradation products.
 Excipient compatibility studies are conducted mainly to predict the potential incompatibility of the drug in the
final dosage form.
 These studies also provide justification for selection of excipients, and their concentrations in the formulation as
required in regulatory filings.
 There fillings has also been an increased regulatory focus on the Critical Quality Attributes (CQA) of excipients
and their control strategy, because of their impact on the drug product formulation and manufacturing process
which enhanced due to increasing QbD trend.
Compatibility tests are categorised as:
1. Compatibility test for solid state reactions
much slower and difficult to interpret
2. Compatibility test for liquid state reactions
easier to detect
According to Stability Guidelines by FDA,
following conditions should be evaluated for solutions
or suspensions:
1. Acidic or alkaline pH
2. Presence of added substances
3. High oxygen and nitrogen atmospheres
4. Effect of stress testing conditions
Typical Modalities of Compatibility Testing
a) Study Execution
b) General Steps and decisions
 General Steps in Compatibility Studies:
1. Experimental Design
 2. Sample preparation
3. Storage
4. Sample Analysis & Data Interpretation
 I. Experimental Design
The design of experiments is governed by the potential formulation choices, and excipient preferences.
These decisions are made in conjunction with all the other available preformulation data, API
characteristics, and marketing preferences.
These also determine the types of pharmaceutical excipients that are evaluated.
Ex: compatibility studies for a liquid formulation of an insoluble compound would differ widely, and
include excipients such as surfactants and suspending agents, from the studies designed for a highly
soluble compound.
Compatibility studies are commonly carried out by accelerated stress testing, and evaluation of its effect on
the binary or multicomponent drug–excipient mixtures.
Designs:
Two- or Multi-component Systems
 Binary mixtures of drug and common pharmaceutical excipients
such as diluents or ternary mixtures of drug, a diluent, and excipients
used in lower proportions such as disintegrants and lubricants.
And are incubated at accelerated conditions of temperature and
humidity for extended periods of time, using drug alone and excipient
alone as controls.
Incompatibilities are physically identified by
> Visual observation for color or physical form changes,
>Spectroscopic and calorimetric methods, and
>Chemically quantified by analytical assays for drug content and
impurities.
n-1 Design & Mini formulations
Compatibility studies are often aimed at solving
formulation stability issues.
In such cases studies are carried out with the exclusion
of only one component in each sub-lot to identify the
source of incompatibility.
Often, mini-formulations are prepared with the
exclusion of non-critical, quantitatively minor, and/or
easily interchangeable ingredients, e.g., colors and
flavors, from solutions and suspensions.
 II. Sample Preparation
a. For solid state reactions:
Sample A: -mixture of drug and excipient
Sample B: -Sample + 5% moisture
Sample C: -Drug itself without excipients
All the samples of drug-excipient blends are kept for 1-3 weeks at specified storage conditions.
 Then sample is physically observed.
 It is then assayed by TLC or HPLC or DSC
 Whenever feasible, the degradation product are identified by MASS SPECTROSCOPY, NMR or other
relevant analytical techniques.
b. For liquid state reactions:
 Place the drug in the solution of additives.
 In case of oral liquids, compatibility with ethanol, glycerin, sucrose, preservatives and buffers are
usually carried out.
 Both flint and amber vials are used.
 This will provide information about
Susceptibility to oxidation,Susceptibility to light exposure,Susceptibility to heavy metals.
. Storage Conditions
 The storage conditions used to examine compatibility can vary widely in term of temp. & humidity,
but a temp. of 50°C for storage of compatibility sample is considered appropriate.
 Some compounds may require high temp. to make reaction proceed at a rate that can be measured
over a convenient time period.

Sample Analysis & Data Interpretation

 Monitoring Drug Degradation
Thermal Methods (DSC, DTA, etc.)
 Monitoring to form changes
PXRD, ssNMR, NIR spectroscopy, etc.
 Data analysis
MILLIARD REACTION
Amine+reducing sugar cond
water+ketosamine 5 hydroxymethyl-
2furaldehyde
 Stability testing

Establish a re-test period for the drug substance or a shelf life for the drug product and recommended
storage conditions.

Stability Studies are preformed on ...

 Drug Substances (DS)  The unformulated drug substance that may
subsequently be formulated with excipients to produce the dosage form.

 Drug Products (DP)  The dosage form in the final immediate packaging
intended for marketing…….

controlled and documented determination of acceptable changes of the drug substance

or drug product
 Arrhenius Equation
 K = Se-Ha /RT
where..k = specific rate of degradation.
R = gas constant ( 1.987 calories degree -1mole)
T = absolute temperature.
S = frequency factor.
Logarithmically ,

ln k = -Ha/ RT + ln S

converting to log 10

Log k = -ΔHa/2.303 R .1/T + log S

log k = specific rate of degradation
S = constant
 Plot of log K v/s 1/T….yields a slope equal to -ΔHa/2.303 R ….. From which heat of activation (ΔHa) can be
calculated.

 Log k2/k1 = ΔHa/2.303 R . ( T2 – T1 )/ T2.T1

 Stability studies at different stages

􀂄 Selection of samples
• API, excipient, batches
􀂄 Scope
• Appearance
• Appropriate physical-chemical
parameter
• Assay / Degradation products
􀂄 Up to 3 month

Scope
• Determination of expire date
Scope • Determination of preliminary
• Solubility Profile specifications
• Hygroscopicity • Release of clinical batches
• Thermal stability • Monitoring of samples during the clinical
(Melting point, phases
Polymorphism) • Definition of storage conditions
• Chemical stability • Definition of Tests for registration
􀂄 1 Batch stability
􀂄 Up to 3 month 􀂄 Up to 36 month
 Theories of dispersion
Solid – Dispersion System
Definition
1. Solid dispersion is defined as dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared
by the melting, solvent or melting solvent method.
1. Molecular diffusion: obeys ficks first law and 2nd law of diffusion

2. Fick's first law relates the diffusive flux to the concentration under the assumption
of steady state.
3. J= -D(dS / dx)
4. j= flux, D = diffusivity , S= is concentration
5.
Fick's second law predicts how diffusion causes the concentration to change with
time. It is a partial differential equation which in one dimension reads:

where
•φ is the concentration in dimensions of [(amount of substance) length−3], example
mol/m3; φ = φ(x,t) is a function that depends on location x and time t
•t is time [s]
•D is the diffusion coefficient in dimensions of [length2 time−1], example m2/s
•x is the position [length], example m
Fick's second law predicts how diffusion causes the
concentration to change with time. It is a partial differential
equation which in one dimension reads:
dY/dT= D (d2Y/d2x)
where
•φ is the concentration in dimensions of [(amount of
substance) length−3], example mol/m3; φ = φ(x,t) is a function
that depends on location x and time t
•t is time [s]
•D is the diffusion coefficient in dimensions of [length2 time−1],
example m2/s
•x is the position [length], example m
Mechanical dispersion:
because of the variations in the microscopic velocity within each flow channel
and from one channel to another. spreading is present
Eddy diffusion : the mixing process that is due to the random fluctuation of
fluid mass or the occurrence of eddies in the condition described as turbulent
flow ,exist in porous media in slight extent more in large particles

Mixing due to structural control: the apparent mixing mechanism due to large-scale
structural variations in the granular material These variation scontrol the direction of
movement of a given fluid particle; hence, if an average concentration is taken along a given
plane parallel or transverse to the direction of flow, a large-scale mixing is observed
 1.Adsorption:
a process which differs from the others in that the amount of
mass transported depends on the physicochemical interaction of
the transported substance and the solid of the medium.
The existence of an unbalanced force field causes migration of a
liquid-borne contaminant from the liquid to the solid surface
In some instances the contaminant is permanently fixed on the
surface,whereas in others it moves continuously from
liquid to solid, or vice versa
Emulsion
An emulsion is a mixture of two or more liquids that are normally immiscible (unmixable or
unblendable). Emulsions are part of a more general class of two-phase systems of matter called colloids
In an emulsion, one liquid (the dispersed phase) is dispersed in the other (the continuous phase).
for example vinaigrettes,
homogenized milk,
mayonnaise, and
some cutting fluids for metal working.
Multiple emulsions are also possible, including a "water-in-oil-in-water" emulsion and an "oil-in-water-
in-oil" emulsion
The droplets dispersed in the liquid matrix (called the “dispersion medium”) are usually assumed to
be statistically distributed.
 Instability[edit]
 Emulsion stability refers to the ability of an emulsion to resist change in its
properties over time. There are four types of instability in
emulsions: flocculation, creaming, coalescence, and Ostwald ripening. An
everyday example of Ostwald ripening is the re-crystallization of water
ice cream which gives old ice cream a gritty, crunchy texture. Larger ice
crystals grow at the expense of smaller ones within the ice cream, creating
coarser texture
 Flocculation occurs when there is an attractive force between the droplets,
they form flocs, like bunches of grapes. Coalescence occurs when droplets
bump into each other and combine to form a larger droplet, so the
droplet size increases over time. Emulsions can also undergo creaming,
where the droplets rise to the top of the emulsion under the influence
of buoyancy, or under the influence of the centripetal force induced when
a centrifuge is used.
 An appropriate "surface active agent" (or "surfactant") can increase the
kinetic stability of an emulsion so that the size of the droplets does not
change significantly with time. It is then said to be stable.
Mechanisms of emulsification:
A number of different chemical and physical processes and mechanisms
can be involved in the process of emulsification:
Surface tension theory – according to this theory, emulsification takes
place by reduction of interfacial tension between two phases
Repulsion theory – the emulsifying agent creates a film over one phase
that forms globules, which repel each other. This repulsive force causes
them to remain suspended in the dispersion medium
Viscosity modification – emulgents like acacia and tragacanth, which are
hydrocolloids, as well as PEG (or polyethylene glycol), glycerine, and other
polymers like CMC (carboxymethyl cellulose), all increase the viscosity of
the medium, which helps create and maintain the suspension of globules
of dispersed phase
suspension is a heterogeneous mixture containing solid particles that are sufficiently large
for sedimentation
suspension is a heterogeneous mixture in which the solute particles do not dissolve but get suspended
throughout the bulk of the medium
A suspension of liquid droplets or fine solid particles in a gas is called an aerosol or particulate. In
the atmosphere these consist of fine dust and soot particles, sea
salt, biogenicand volcanogenic sulfates, nitrates, and cloud droplets.

a significant thermodynamic problem in suspension formulation comes from Ostawald ripening , crystals
growth not because of phase change ,but as a result of the difference in the solubility as a function of crystal
size
RT/M ln(S2/S1)= 2a/p{1/r1 -1/r2}
R gas contant
T absolute temperature
M mol.wt of solute mol.
a specific surface
r1 and r2 is radious of particle
 preparation and stability Large and small
volume parental
 definition of parenterals
Parenterals are those preparations intended for
injection through the skin or other external boundary tissue,
rather than through the alimentary canal, so that the active
substances they contain are administered using gravity or
force directly into a blood vessel, organ, or tissue.
Necessities of parenteral preparations:

Sterility (must)

Free from pyrogen (must)

 Parenterals are those preparations intended for
injection through the skin or other external boundary
Free from particulate
tissue, matter
rather than through the alimentary canal, so
that the active substances they contain are
administered using gravity or force directly into a
Clarity (must)
blood vessel, organ, or tissue.

Stability (must)
 Isotonicity (should)

 Solvents and vehicles used must meet special purity

and other standard

 Do not use coloring agents

 Must be prepared under aseptic conditions

 Specific and high quality packaging

MANUFACTURING PROCESS:

• A suitable test method for the preservative properties of the formulation are
provided under Efficacy of antimicrobial preservation.

• Methods designed to ensure sterility and to avoid the introduction of

contaminants and the growth of micro-organisms follow the method of
sterilization.

• Water used in the manufacture of parenteral preparations complies with the

requirements of water for injections

• The design and maintenance of the equipment and the method of

manufacture must be such as to ensure the stability of the active substance
and of the final product and sterility of the injection.
 PARENTERAL PREPARATIONS

 DEFINITION:
Parenteral preparations are sterile preparations which may consist of one or more active
ingredients intended for administration by injection, infusion or implantation into the body.

 REQUIRED EXCIPIENTS:
• Solvents
• substances to enhance solubility
• suspending agents
• buffering agents
• substances to make the preparation isotonic with blood
and
• stabilizers or antimicrobial preservatives
 TESTS
• Parenterals are tested for particulate contamination: sub-visible
particles.

• For preparations for human use, solutions for infusion or solutions for
injection supplied in containers with a nominal content of more than
100 ml comply with the test.

• Sterility. Parenteral preparations comply with the test for sterility.

Formulation of parenteral products

 In the preparation of parenteral products, the following substances are added to make a stable
preparation:
 The active drug
 Vehicles
Aqueous vehicle (e.g. water for injection, water for injection free from CO2 )
Non-aqueous vehicle (e.g. Ethyl alcohol, propylene glycol, almond oil)
 Adjuvants
Solubilizing agents (e.g. Tweens & polysorbates)
Stabilizers & antioxidants (e.g. thiourea, ascorbic acid, tocopherol)
Buffering agents (e.g. citric acid, sodium citrate)
Antibacterial agents (e.g. benzyl alcohol, metacresol, phenol)
Chelating agents (e.g. EDTA)
Suspending, emulsifying & wetting agents (e.g. MC, CMC)
Tonicity factor (e.g. sodium chloride, dextrose)
 Formulation of SVP :
 Aqueous vehicle :
Types :- purified water, WFI, sterile WFI, bacteriostatic WFI, sterile WF
Irrigation.
Preparation :- Distillation, ion exchange or reverse osmosis.
Except purified water all are pyrogen free

Non aqueous vehicle :

 Because of safety
purity
biocompatibility
 Several SVPs are marketed as oily solutions
The oil must be vegetable in origin (sesame, olive, or cottonseed oil).
Product USP Oil
Ampicillin(suspension) Vegetable
Diethyl stilbestrol Sesame, cotton
Epinephrine(suspension) Sesame
Penicillin G procaine Vegetable
(suspension)

Co solvents :-
Are used to increase the stability of poorly soluble drug in water and
and prevent drug chemical degradation by hydrolysis.
Eg. propylene glycol or in combination with ethanol and polyethylene
glycol.
Ingredients or added substances
 Antimicrobial preservatives :
Maintain the stability of the product during storage.
Phenylmercuric nitrate and Thimerosal 0.001% , Benzethonium
chloride 0.01%, Benzyl alcohol 0.5- 10.0%, Phenol or cresol 0.5%,
chlorobutanol 0.5%.

 Buffers :
Added to maintain pH Results in stability of drug against hydrolytic
degradation or enhance the solubility of drug in solution.
Common buffers used in SVPs
pH Buffer system Conc. %
3.5-5.7 Acetic acid-acetate 0.22
2.5-6.0 Citric acid-citrate 0.5
6.0-8.2 Phosphoric acid- 0.8-2
phosphate
8.2-10.2 Glutamic acid- 1-2
glutamate

Antioxidants :
Antioxidants function by preferentially with molecular oxygen and minimizing or
terminating the free radical auto-oxidation reaction.
eg. Reducing agents: Ascorbic acid 0.02-0.1%, Sodium Bisulfite 0.1-0.15%,
Thiourea 0.005%
Blocking agents: Ascorbic acid esters 0.01-0.015%, Tocopherols 0.05-0.075%
Tonicity adjusters :
Electrolytes: Nacl
Non electrolytes: Glucose, Mannitol, Glycerine
Eg. Of isotonic: Dextrose injection 5% & Nacl injection 0.9%

Some solutions are iso-osmotic but not isotonic this is because

the physiology of the cell membranes must be considered.
For eg. the cell membrane of the RBC is not semi- permeable to
all drugs it allows ammonium chloride, alcohol, boric acid,
glycerin, propylene glycol, and urea to diffuse freely.
In the eye the cell membrane is semi permeable to boric acid
a 2% solution is an isotonic ophthalmic solution.
But even though a 2% solution of boric acid is an isotonic with
the eye and is iso-osmotic, it is not isotonic with blood since
boric acid can freely diffuse through the RBC– and it may cause
HEMOLYSIS.
Tonicity can be measurement by: osmometer

Other ingredients :
Bulking agents – for freeze dried preparations(solids) eg
mannitol, lactose sucrose, dextrose.
Suspending agents – Carboxy methyl cellulose, sorbitol.
Emulsifying agents – lecithin, polysorbate 80
Ophthalmic ointments bases – petrolatum.
 Manufacturing of parenterals

 The production area where the parenteral preparation are manufactured

can be divided into five sections:

 Clean-up area

 Preparation area

 Aseptic area

 Quarantine area

 Finishing,lebelling & packaging area

Clean-up area:
 It is not aseptic area.

 All the parenteral products must be free from foreign particles & microorganism.

 Clean-up area should be withstand moisture, dust & detergent.

 This area should be kept clean so that contaminants may not be carried out into aseptic area.

Preparation area:
 In this area the ingredients of the parenteral preparation are mixed & preparation is made for filling operation.

 It is not essentially aseptic area but strict precautions are required to prevent any contamination from outside.
Aseptic area:
 The parenteral preparations are filtered, filled into final container & sealed
should be in aseptic area.
 The entry of personnel into aseptic area should be limited & through an
lock.
 Ceiling, wall & floor of that area should be sealed & painted.
 The air in the aseptic area should be free from fibers, dust and
microorganism.
 The High efficiency particulate air filters (HEPA) is used for air.
 UV lamps are fitted in order to maintain sterility.
Quarantine area:
>After filling, sealing & sterilization the parenteral product are
held up in quarantine area.
>Randomly samples were kept foe evaluation.
>The batch or product pass the evaluation tests are transfer in to
finishing or packaging area.
Finishing & packaging area:
Parenteral products are properly labelled and packed.
Properly packing is essential to provide protection against
physical damage.
The labelled container should be packed in cardboard or plastic
container.
Ampoules should be packed in partitioned boxes
EVALUATION OF PARENTERAL PREPARATIONS

The finished parenteral products are subjected

to the following tests, in order to maintain
quality control:
A) sterility test
B)clarity test
C)leakage test
D)pyrogen test
E)assay
A) sterility test

It is a procedure carried out to detect and conform

absence of any viable form of microbes in or on
pharmacopeia preparation or product.

1) Method of sterility testing

i ) METHOD 1 Membrane filtration method

ii) METHOD 2 Direct inoculation method

Membrane filtration method (METHOD 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)
 All steps of this procedure are performed aseptically in a Class 100 Laminar Flow Hood
Composition of culture medium for sterility testing
Components Culture medium
Fluid Thioglycollate Soybean- casein

L- cystine 0.5gm -
Sodium chloride 2.5gm 5.0gm
Dextrose 5.0/5.5gm 2.3/2.5gm
Pancreatic digest of casein 15.0gm 17.0gm
Papaic digest of soya bean - 3.0gm
Dibasic potassium phosphate - 2.5gm
Granular agar (moisture<15%) 0.75gm -
Yeast extract (water soluble) 5.0gm -
Sodium thioglycollate or thioglycolic acid 0.5gm or -
0.3ml
Resazurin (0.10%w/v fresh solution) 1.0ml -

Purified water 1000ml 1000ml

 Membrane filter 0.45μ porosity

Filter the test solution

After filtration remove the filter

Cut the filter in to two halves

First halves (For Bacteria) Second halves (For Fungi)

Transfer in 100 ml culture media Transfer in 100 ml culture media

(Fluid Thioglycollate medium) (Soyabeans-Casein Digest medium)

Incubate at 30-350 C for not less then 7 days Incubate at 20-250 C for not less then 14 days

Observe the growth in the media Observe the growth in the media
Direct inoculation method (METHOD 2):

Suitable for samples with small volumes

volume of the product is not more than 10% of the volume of the
medium
suitable method for aqueous solutions, oily liquids, ointments and
creams
Direct inoculation of the culture medium suitable quantity of the
preparation to be examined is transferred directly into the
appropriate culture medium & incubate for not less than 14 days.
B)clarity test

 Particulate matter is defined as unwanted mobile insoluble matter

other than gas bubble present in the product.
 If the particle size of foreign matter is larger than the size of
R.B.C.. It can block the blood vessel.
 The permit limits of particulate matter as per I.P. are follows:
Methods for monitoring particulate matter
contamination:

1) Visual method
2) Coulter counter method
3) Filtration method
4) Light blockage method
C)leakage test
 The sealed ampoules are subjected to small cracks which occur due
to rapid temperature changes or due to mechanical shocks.

Filled & sealed ampoules

Dipped in 1% Methylene blue solution

Under negative pressure in vacuum chamber

Vacuum released colored solution enter into the ampoule

Defective sealing

Vials & bottles are not suitable for this test because the sealing
material used is not rigid
D)pyrogen test

Pyrogen = “Pyro” (Greek = Fire) + “gen” (Greek = beginning).

Fever producing, metabolic by-products of microbial growth and
death.
Bacterial pyrogens are called “Endotoxins”. Gram negative bacteria
produce more potent endotoxins than gram + bacteria and fungi.
 Endotoxins are heat stable lipopolysaccharides (LPS) present in
bacterial cell walls, not present in cell-free bacterial filtrates
Method
 Dissolve the subs being examined in, or dilute it with a pyrogen free
saline solution
 Warm the liquid being examined to approx. 38.5o C temp before
injection
 The volume of injection is NLT 0.5ml/kg & NMT 10ml/kg of body
weight
 Withhold water during test
 Clinical thermometer is inserted into the rectum of rabbit to record
body temp
 2 normal reading of rectal temp are should be taken prior to the test
injection at an interval of half an hr & its mean is calculated- initial
temp
 The solution under test is injected through an ear vein
 Record the temp of each rabbit in an interval of 30 min for 3 hrs
 The difference between initial temp & maximum temp is recorded-
taken as response
Limulus amebocyte lysate [LAL] test

Limulus amebocyte lysate [LAL] test another method for the

determination of pyrogenic endotoxins
In this method the test solution is combined with a cell lysate from
the ameabocyte [blood cells] of horse shoe crab
Any endo toxin that might be present will be coagulated with
protien fraction of the ameabocytes and results in the formation
of a gel
This consider to be simple,rapid and of greater sensitivity that the
rabbit test
E)assay

Assay is performed according to method given In the

monograph of that parental preperation in the
pharmacopoeia
Assay is done to check the quantity of medicament
present in the parenteral preperation
References

 Lachman/Lieberman’s “The Theory and Practice Of Industrial

Pharmacy” Fourth Edition 2013, Edited by: Roop K Khar, SP Vyas,
Farhan J Ahmad, Gaurav K Jain, CBS Publishers and Distributors Pvt
Ltd, New Delhi.
 Doornbos C and Hann P. Optimization Techniques in Formulation and
Processing. In Encyclopedia of Pharmaceutical Technology. Swarbrick J
and Boylan JC, Eds., Vol. II, Marcel Dekker, New York. 199
 Modern Pharmaceutics Fourth Edition, Revised and Expanded, Edited
By G.S.Banker & C.T.Rhodes, Marcel Dekker pg387-389.
 The Science & practice of Pharmacy, By Remington, Vol-01, 21st
Edition, Lippincott Publication, pg-838-840.
Thank you