DISSOLUCTION

TEST APPARTUS
DESIGNS
BY
CHETAN N K
1ST YEAR M PHARMA
DEPARTMENT OF INDUSTRIAL PHARMACY
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CONTENTS

• Introduction

• Purpose of dissolution apparatus

• Types of resolution accordance

• Dissolution media

• Referance

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 INTRODUCTION
•Purpose: Measures drug release from solid dosage forms.
•Significance: Critical for pharmaceutical development and quality control.
•Mechanism: Simulates drug dissolution in the body using a liquid medium.
•Standardization: USP and other pharmacopeias define standardized apparatus and
procedures.
•Types: Various apparatus exist (e.g., paddle, basket, flow-through cell) to suit different
dosage forms.
•Control: Precise control of temperature, agitation, and medium is essential.
•Outcome: Provides data on the rate and extent of drug dissolution.
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 What is Dissolution Apparatus ?
Tablet Dissolution is a standardized method for measuring the rate Of drug release from a
dosage form. In the pharmaceutical industry, drug dissolution testing is routinely used to
provide critical in vitro drug release information for both quality control purposes,

i.e., to assess batch-to-batch consistency of solid oral dosage forms such as tablets, and drug
development, i.e., to predict in vivo drug release profiles.

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 Purposes of Dissolution Apparatus Test:

Quality-control and quality-assurance purposes

In early phase drug development

Assess product stability, monitor formulation changes over time

Establish in-vitro—in-vivo correlations "IVIVC"

Regulatory perspective Particularly in the development and approval of generic dosage

forms

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Different types of dissolution apparatus to the
pharmacopeia

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 USP Dissolution apparatus
Apparatus 1: Basket type
• Vessel – made up of borosilicate glass – semi hemispherical
bottom – capacity 1000ml

• Shaft-stainless steel 316-rotates smoothly with out

significance wobble 9

• Basket-stainless steel 316-gold coating up to 0.0001 inch

• Water bath –maintained at 37± 0.5°c

• Used for :capsules, tablets, delayed release suppositories,

floating dosage forms
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The roaatating basket apparatus consists of cylindrical basket held by a motor shaft.

The basket holds the sample end rotates in a round flask containing the dissolution medium.

The entire flask is immersed in a constant-temperature bath set at 37'C. The rotating speed

and the position of the. Basket must meet specific requirements set forth in the current OSR

The most common rotating speed for the basket method is_ 100 rpm.

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 USP APPARATUS 2: PADDLE TYPE

[Link] : made up of borosilicate glass

[Link]: The blade passes through shaft so that bottom of

blade fuses with bottom of shaft

[Link] elements : Made of Tenon For

laboratory purpose Stainless steel.

[Link]-bath : Maintain at 37±0.5°c.

[Link]: Platinum wire used to prevent capsule 'tablet from

floating.

used For. Capsules, Powders, Suspensions. Tablets

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• The paddle apparatus consists of a special. coated paddle that minimizes turbulence due to
stirring.
• The paddle is attached vertically to a variable-speed motor that rotates at a controlled speed.
• The tablet or capsule is placed into the round-bottom dissolution flask, which minimizes
turbulence of the dissolution medium.
• The apparatus is housed in a constant-temperature water hall maintained at 37°C, similar to the
rotating-basket method.
• The position and alignment of the paddle are specified in the USP. The paddle method is very
sensitive to tilting. Improper alignment may drastically affect the dissolution results with some
drug products.
• The most common operating speed for Apparatus are 50 rpm for solid oral dosage forms and 25
rpm for suspensions.
• Apparatus l' is generally preferred for tablets. A sinker, such as a few turns Of platinum wire,
used to prevent a capsule or tablet from floating.

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• USP Apparatus 3:
Reciprocating cylinder
Vessel :Cylindrical flat bottom glass
vessel.

Agitation type: Reciprocating -

Generally 5-35 rpm. 30cycle/sec

Volume of dissolution fluids :200-

250 ml.

 Water bath: Maintain at 37±0.5°c.

 Used for : extend release tablets

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The USP Apparatus 3 is considered as the first line apparatus in product devilment of
controlled release preparations. because of its usefulness and convenience in exposing
products to mechanical as well as a verity of physicochemical conditions which may
influence the release of products in the GI tract
The particular advantage of this apparatus is the technically easy and problem free use of test
solutions with different pH values for each time interval.
It also avoids cone formation for disintegrating (immediate release) products, which can be
encountered with the USP apparatus ll.
An additional advantage of apparatus Ill includes the feasibility of drug-release testing of
chewable tablets. Chewable tablets for human use do not contain disintegrants , so they need
to undergo physiological grinding (i.e., chewing) prior to dissolution.
For example. enteric-coated/sustained release dosage forms. and also offers the advantages of
mimicking the changes in physiochemical conditions and extraordinarily strong mechanical
forces experienced by the drug products in the mouth or at certain locations in the Gi tract,
Such as the pylorus and the ileocecal valve.

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• Apparatus Type 4:
Flowthrough Cell

Reservoir: For dissolution medium.

Pump: Forces dissolution medium through the cell,

holding the sample.

Flow rate: 240-960 mL/hr.

Laminar flow is maintained.

Water bath: Maintains at 37 ± 0.5°C.

Used for : Tablets, capsules, or granules.

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FLOW THROUGH CELL

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• TYPES
Closed-mode : where the fluid is re-circulated and by necessity is of fixed volume

Open-mode : when there is continuous replenishment of the fluids

Advantages

Ease of maintaining sink condition during dissolution of which is often required for drugs
having limited aqueous solubility

Feasibility of using large volume of dissolution fluid

Feasibility of automation of apparatus

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The Paddle Over Disc Method (USP Apparatus 5)

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• Dissolution Vessel: A cylindrical glass or appropriate material vessel that holds the dissolution
medium, ensuring proper immersion of the sample
• .Dissolution Medium: Typically water, buffer solution, or simulated gastric fluid, chosen based
on the dosage form's properties. Volume ranges from 500 to 1000 mL
• .Paddle: Positioned above the disk, rotating at 50-75 rpm to agitate the dissolution medium,
ensuring uniform mixing and preventing sedimentation
• Disc: A flat, horizontal disk (usually stainless steel) placed above the medium to hold the
dosage form in place during dissolution
• .Temperature Control: The dissolution medium is maintained at 37°C ± 0.5°C, simulating
physiological conditions of the gastrointestinal tract.
• Procedure for the Paddle Over Disc Method (USP Apparatus 5)
• Step 1: Setup of the Apparatus Dissolution Vessel Setup: Position the dissolution vessel on the
apparatus. The vessel is typically filled with dissolution medium to a specified volume, usually
500-1000 mL. The volume should be sufficient to allow proper immersion of the sample
while also facilitating adequate flow of the medium around the dosage form.
• Temperature Adjustment : Ensure that the dissolution medium is pre-heated to the required
temperature of 37°C ± 0.5°C to simulate the human body’s conditions 21
• Step 2: Sample Preparation Placing the Disk: Place a flat disk on the bottom of the vessel.
The disk should be made of a non-reactive material (usually stainless steel or similar) to
avoid interaction with the dissolution medium or sample .Place the dosage form (e.g., tablet,
capsule, controlled-release dosage form) on top of the disk. The disk helps to keep the sample
in position and ensures consistent exposure to the dissolution medium, avoiding floatation or
dislodgement during the test.
• Step 3: Paddle Settings Paddle Placement: Position the paddle above the disk at the
appropriate distance. The typical distance between the paddle and the disk is around 2.5 cm
(depending on the specifications for the specific test). The paddle is then set to rotate at the
specified speed. Rotation Speed: The paddle speed is usually set to 50 rpm or 75 rpm
depending on the method's requirements. This rotational speed provides agitation and ensures
that the dissolution medium is mixed effectively without disturbing the position of the dosage
form.
• Step 4: Dissolution Process Start the Test: Begin the test by activating the paddle to rotate.
The paddle's rotation agitates the dissolution medium, promoting the dissolution of the drug
from the sample. The disk helps ensure that the sample stays in place, allowing for uniform
Test: Begin predefined intervals (such as 5, 10, 15, 30, and 60 minutes), a sample of the
dissolution medium is withdrawn using a pipette or a sampling syringe. The sampling
intervals are chosen based on the expected release profile of the drug and the method 22
specifications.
 ROTATING CYLINDER USP APPARATUS 6

• structure to hold dosage forms This apparatus is

used to test transdermal patches and is similar to
Apparatus 1. However, instead of a rotating
basket, there is a rotating cylinder.
•The patch is generally attached to a piece of
Cuprophan (a dialysis membrane material like
cellulose acetate) and glued to the outside of the
cylinder.
•The system is then lowered into a specified volume
of medium (typically 900 mL) that is held at a
constant 32ºC ± 0.5 ºC and rotated at a constant rate
until the active ingredient from the patch has passed
into solution.

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• USP APPARATUS 7 RECIPROCATING HOLER
• Reciprocating Holder (Test Vessel): The apparatus consists of a single or multiple reciprocating
holders (test vessels) which are cylindrical in shape. Each holder is designed to hold the drug
dosage form during testing.
• Medium Reservoir: Each reciprocating holder is filled with an appropriate dissolution
medium (such as water, buffer solutions, or simulated gastric or intestinal fluids). The volume is
generally about 500–1000 mL per test vessel.
• Reciprocating Motion: The core feature of this apparatus is its reciprocating motion, which
allows the test holders to move back and forth along a horizontal axis. The motion mimics the
peristaltic movements in the human gastrointestinal tract, thus simulating the flow of gastric or
intestinal fluid.
• Cycle and Speed: The reciprocating motion typically has an adjustable stroke length and
frequency, usually set to 30–50 cycles per minute (depending on the specific test conditions and
formulation). The stroke length (the distance the holder moves in each cycle) can also be
adjusted to simulate various levels of gastrointestinal motility.
• Temperature Control System:To maintain the dissolution medium at 37°C (±0.5°C), the apparatus
incorporates a temperature control system. This is typically done using a water bath or heated jacket
around the vessel holding the dissolution [Link] temperature control is crucial to ensuring
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that the dissolution process proceeds under consistent, physiological conditions.
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• DISULUCTION MEDIA
• Is the processes by which solid substance enters the solvent phase to yield a solution i.e. mass
transfer from solid surface to liquid phase
• SELECTION OF DISSOLUTION MEDIA:I
• The selection of an appropriate dissolution medium is a fundamental stage of the dissolution
test.
• It is more important that the test closely simulate the environment in the Gl tract than
necessarily produce sink condition.
• SINK CONDITION:
• The dissolution rate may be given by Novey-Whitney equation.

• Where, S : surface area

• t: time
• Cs-Ct: concentration gradient between the concentration of solute in the stagnant layer
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• dW/dt= K
•This represents that the dissolution rate is constant under sink conditions.
• We have to maintain sink condition in in-vitro. This is can be achieved by,
• Bathing the dissolving solid in fresh solvent from time to time,
• Increasing the volume of dissolution fluid.
Adding a water miscible solvent such as alcohol to the dissolution medium.
By adding selected adsorbent to remove the dissolved drug

OPERATING PARAMETERS

[Link]:
• The recommended volume Of dissolution medium is 900ml when using the basket or paddle
apparatus.
• The volume can be raised to between 2 and 4 L, depending on the concentration and sink
conditions of the drug solution.
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 [Link]:
• The standard temperature for the dissolution medium is 37±0.50C for oral dosage forms.
• Slightly increased temperatures such as 38±0.50C have been recommended for dosages forms
such as suppositories.
• Lower temperatures such as 32±0.5 0C are utilized for topical dosage forms such as
transdermal patches and topical ointments. .
3 .DEAERATlON:
• Air bubbles can interfere with the test results.
• Bubbles on the dosage unit may decrease the dissolution rate by decreasing the available
surface area.
• Some formulations will be sensitive to the presence of dissolved air in the dissolution.
• Media containing surfactants are not usually deaerated after the surfactant has been added to
the medium.
• Media containing surfactants are not usually deaerated after the surfactant has been added to
the medium because Of excessive foaming.
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• [Link] DISSOLUTION MEDIA:
SIMULATED GASTRIC FLUID:
•The traditional medium to simulate gastric conditions in the fasted state has been simulated
gastric fluid (SGF).
•This medium contains HCL and Nacl , as well as pepsin and water, and has a pH Of 1.2.
•Although the medium addresses many Of the qualities Of gastric juice.
•For example, most studies of gastric pH indicate that the across-the-board average gastric pH
usually lies in the rangel.5—1.9 .
WATER
•Water is an attractive medium that because of its simplicity has been widely used for quality
control purposes.
•It could even be argued that itis physiologically relevant since many formulations are intended to
be ingested with a glass Of water.
•However, the pH Of water may vary with its source, and water has no buffer capacity.

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SIMULAED INTESTINAL FLUID
•A frequently used medium for the simulation of small intestinal (SI) conditions in the fasted
state is simulated intestinal fluid (SIF)
•A medium that was first described as standard test solution in the USP more than 50 years ago.
•The only parameter that has been changed is the pH of the medium.
•As it was assumed that the pH in the small intestine is very close to blood plasma, the pH of SIF
was initially set at 7.5.
• The dissolution characteristics Of Oral formulations should be evaluated over the physiologic
pH range of 1.2-6.8.
BIORELEVENT MEDIA
• Biorelevant is short for 'biologically relevant'.
• Biorelevant media are virtually the same as intestinal juices. They contain key natural
surfactants (bile salts, phospholipids) present in intestinal juices. These are missing from
ordinary dissolution media.
• They are virtually the same as the fluids inside the body, it can provide a much more accurate
picture of how drugs and their formulations are likely to dissolve in vivo.
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• Advantages of Biorelevant Media
[Link] Human GI Conditions: Mimic the pH, enzymes, and bile salts of the
stomach and intestines, providing more accurate predictions of drug behavior.
[Link] Drug Absorption Prediction: Helps forecast how a drug will dissolve
and be absorbed in the human body, improving bioavailability assessments.
[Link] Formulation Development: Identifies solubility and permeability issues
early, optimizing drug formulations before clinical trials.
[Link]-Effective: Reduces the need for expensive animal testing and clinical studies,
saving time and resources.
[Link] Compliance: Meets FDA and EMA guidelines, making it easier to gain
approval for new drug applications.
[Link] for Specific Drugs: Tailored to simulate specific conditions based on
a drug's properties (e.g., solubility, stability), enhancing drug testing accuracy.
[Link] in Bioequivalence Studies: Essential for comparing generic drugs to
branded counterparts, ensuring similar therapeutic effects. 31
• Biorelevant Dissolution Media
• Key Parameters in Biorelevant Media:
• Biorelevant dissolution media simulate the conditions in the gastrointestinal (GI) tract,
particularly in the stomach and small intestine, to predict the in vivo behavior of poorly soluble
drugs. Important parameters of biorelevant media include:
[Link]: The pH of the media should mimic the environment of the stomach (acidic in the fasted
state) or the small intestine (alkaline in the fasted and fed states).
[Link]: Mimics the osmotic pressure found in the GI tract, affecting drug solubility and
dissolution.
[Link] : Surfactants like bile salts and phospholipids are included to reduce surface
tension, improve wetting behavior, and enhance the solubility of poorly soluble drugs.
[Link] in Biorelevant Media:
1. Bile Salts: Play a significant role in solubilizing lipophilic drugs. Sodium taurocholate is
commonly used to mimic the bile salts in human bile.
2. Phospholipids: They are important for forming micelles, which help solubilize
hydrophobic compounds, and mimic the presence of natural phospholipids in the GI tract.
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• Fasted State Simulated Media:
[Link] (FaSSGF - Fasted State Simulated Gastric Fluid):
1. Composition: Typically, 0.1 N HCl is used. However, it lacks physiological relevance in
terms of surface tension.
2. Recent Improvements: Researchers have added surfactants like taurocholate and
phospholipids to make the medium more biorelevant (FaSSGF).
3. Surface Tension: Adjusted by adding low levels of surfactants (e.g., taurocholate,
phospholipids) to achieve a surface tension closer to what is found in vivo.
4. pH: Adjusted to 1.6 (a more accurate value compared to the commonly used pH of 1.2),
which improves predictions of drug dissolution in the stomach.
[Link]: The use of FaSSGF was shown to improve predictions for drugs like lipophilic weak
bases (e.g., GR253035X), but showed no impact on non-ionizable drugs like atovaquone.
[Link] Small Intestine (FaSSIF - Fasted State Simulated Intestinal Fluid):
1. Composition: Developed by Dressman et al. in the late '90s, FaSSIF includes:
[Link] Salts: Sodium taurocholate.
[Link]: Egg phospholipid, mimicking human bile.
[Link]: Initially, KCl was used to enhance osmolarity, but NaCl was later preferred
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for better physiological relevance.
 1. Buffer Capacity: FaSSIF has been noted to have a significantly higher buffer capacity
compared to human intestinal fluids.
[Link] has become a standard for simulating dissolution in the fasted state and has shown to
improve the dissolution of most BCS (Biopharmaceutical Classification System) class II
drugs (poorly soluble but highly permeable).
• Fed State Simulated Media:
[Link]:
1. Challenges: The composition of stomach contents in the fed state varies depending on the
food ingested, making it difficult to standardize.
2. Milk-Based Media: Initially, milk (3.5% fat) was used to simulate fed conditions due to its
resemblance to typical western diets. However, milk’s osmolality and buffer capacity are
not suitable for accurate simulation.
3. Nutritional Drinks: Media like Ensure Plus and Nutrison have been used to simulate the fed
state in the stomach, with pH and osmolality adjusted to reflect typical post-meal
conditions.
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[Link] Small Intestine (FeSSIF - Fed State Simulated Intestinal Fluid):
1. Composition: Similar to FaSSIF but with higher levels of bile salts and phospholipids.
The pH is adjusted to 5.0, representing the postprandial state.
2. Osmolarity and Buffer Capacity: These parameters are adjusted to simulate the fed state
more accurately, but it has been noted that buffer capacity in FeSSIF is higher than
observed in actual human intestinal fluids after meal intake.
3. Bile Salts and Phospholipids: Same as FaSSIF, sodium taurocholate and phospholipids
are included, but the concentration is increased to reflect the higher bile salt and
phospholipid levels during digestion after a meal.
Use in Food Effect Studies: FeSSIF helps in predicting food effects on drug dissolution. For
example, drugs like troglitazone (an antidiabetic drug) show better dissolution in FeSSIF
compared to FaSSIF, suggesting a potential food effect.

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Comparison of (FaSSIF) – Fasted State Simulated Gastric Fluid and (FeSSIF): Fed
State Simulated Intestinal Fluid

Parameter FaSSIF FeSSIF

pH 6.5 5.0

Osmolarity 270 ± 10 mOsmol 635 ± 10 mOsmol

Buffer Capacity 12 mmol/l/pH 76 mmol/l/pH

Bile Salt 3 mM Taurocholate 15 mM Taurocholate

Phospholipids 0.75 mM Lecithin 3.75 mM Lecithin

NaCl 106 mM 173 mM

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 MEDIA USED IN BIORELEVANT
Media Type Key Components GI Tract Simulation
Simulated Gastric Fluid (SGF) HCl, NaCl, Pepsin, Water Stomach (fasted state)

Fasted State Simulated Gastric Fluid (FaSSGF) Sodium taurocholate, Lecithin, Pepsin, NaCl, HCl, Stomach (fasted state)
Water

Fed State Simulated Gastric Fluid (FeSSGF) NaCl, Acetic acid, Sodium acetate, Milk or acetate Stomach (fed state)
buffer, HCl, water

Simulated Intestinal Fluid (SIF) Electrolytes, Water Small intestine

Fasted State Simulated Intestinal Fluid (FaSSIF) Sodium taurocholate, Lecithin, NaH2PO4, NaCl, Upper small intestine (fasted state)
NaOH, Water

Fed State Simulated Intestinal Fluid (FeSSIF) Sodium taurocholate, Lecithin, CH3COOH, NaCl, Upper small intestine (fed state)
NaOH, Water

FaSSIF-V2 Sodium taurocholate, Lecithin, Maleic acid, NaCl, Upper small intestine (fasted state)
NaOH, water

Sodium taurocholate, lecithin, Glyceryl

FeSSIF-V2 monooleate, Sodium oleate, Maleic acid, NaCl, Upper small intestine (fed state)
water
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• Lipophilic Drugs:
• These drugs, which can be weak acids, weak bases, or non-ionized compounds, tend to
dissolve in the lipid fraction of food once it is broken down into microscopic particles
(chyme). Lipophilic drugs are often predissolved in triglyceride droplets when entering the
small intestine.
• For these drugs, it’s especially important to include lipolysis products (such as free fatty
acids and monoglycerides) in the media simulating intestinal fluids. These lipolysis products
help replicate the drug’s behavior in the GI tract after ingestion.
• A study by Sunesen et al. (2005) demonstrated that including lipolysis products in the media
for a non-ionized compound (danazol) allowed for in vivo–in vitro correlation (IVIVC) in
the fed state.
• In general, for non-ionized compounds, the concentration of solubilizers in the medium is
the major determinant for the dissolution rate. In the fasted state, gastric dissolution is often
of minimal importance, so a fasted state intestinal medium would typically suffice.
• In the fed state, lipolysis products should be included in the dissolution media.

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•Weak Acids:
•Weak acids tend to dissolve very slowly at low pH, which occurs in gastric conditions.
Therefore, dissolution in the gastric fluids can be slow.
•For weak acids, FaSSIF (fasted state simulated intestinal fluid) can be used to simulate
dissolution in the small intestine, as it has the necessary surfactants to help with solubility.
•In the fed state, dissolution in the stomach may play a bigger role since the pH is higher
compared to the fasted state. Thus, a fed state gastric dissolution media should also be
considered.

•Weak Bases:
•Weak bases tend to have higher solubility at lower pH values. Therefore, a combination of fasted
gastric and fasted intestinal media is suitable to simulate their dissolution behavior.
•A fed state gastric dissolution media might be less critical for weak bases since the pH is
higher in the fed state, but the increased transit time and surfactant levels can impact the
dissolution. So, a fed state gastric dissolution step might still be relevant.

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• For intestinal dissolution, fed state media containing biorelevant amphiphiles should be used.
Studies (e.g., Kostewicz et al., 2002) showed enhanced dissolution in FeSSIF (fed state
simulated intestinal fluid) compared to FaSSIF for weak bases, indicating the importance of the
elevated bile salt and lecithin levels, as well as the lower pH.

Prediction of In Vivo Formulation Behavior Based on Biorelevant Dissolution Testing: In

Vitro In Vivo Correlation
•In Vitro–In Vivo Correlation (IVIVC):
•The goal is to predict in vivo formulation behavior using in vitro dissolution testing with
biorelevant media. However, IVIVC is challenging due to multiple factors affecting the blood
concentration–time profile.
•A study by Nicolaides and coworkers tested two 2-step biorelevant dissolution models (fasted
and fed states) compared to a compendial model using water and SIFs (Simulated Intestinal
Fluids).
•BCS Class II drugs (poorly soluble, high permeability) were tested, including:
 Troglitazone (log P 2.7; pKa 6.1 and 12.0) , GV150013X (log P 5.4; non-ionizable)
• Atovaquone (log P 5.1; non-ionizable)
•Sanfetrinem Cilexetil (log P 3.0 and 3.1; non-ionizable) 40
•In vitro dissolution data were compared to clinical studies using the respective formulations.
•Fasted State Conditions:
•Water was used for gastric dissolution, and FaSSIF (Fasted State Simulated Intestinal Fluid) was
used for small intestinal dissolution.
•Satisfactory Correlation: Found for Sanfetrinem, but FaSSIF did not show superiority over
compendial media due to its relatively high solubility.
•Atovaquone: Better correlation with the biorelevant model than the compendial model, but still
not fully acceptable.
•GV150013X: Potentially a class IV drug (low solubility, low permeability), making IVIVC
impossible.
•Fed State Conditions:
•Milk was used for gastric dissolution, and FeSSIF (Fed State Simulated Intestinal Fluid) was
used for small intestinal dissolution.
•Satisfactory Correlation: Found for Troglitazone and Atovaquone.
•Sanfetrinem: Did not correlate well in FeSSIF, suggesting that gastric emptying might limit
intestinal absorption, indicating it’s a borderline low solubility drug.
•No difference between compendial media and FeSSIF was observed for Sanfetrinem, pointing
out the importance of considering gastric emptying as a limiting factor. 41
42
REFERANCE
• United State Pharmacopoeia, The National Formulary, 2002, 20thEdition,
United State Pharmacopoeial Convention INC, Washington,711, 2011.
• INDIAN PHARMACOPOEIA 2007 Volume 1, The IndianPharmacopoeia
Commission, Ghaziabad, 179-181.
• Remington, The Science And Practice of Pharmacy, Volume 1,
21stEdition, Indian Edition, B. I. Publications Pvt. Ltd., 654-665.
• Banakar, U.V. 2000, Pharmaceutical Dissolution Technologies,volume 49.
Marcel Dekker INC, N.Y., 174-175,280.
• Subramanyam C.V.S. 2006, Textbook Of Physical Pharmaceutics,
2ndEdition, Vallabh Prakashan, Delhi, 88-90.
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