팔마텍 Final Summary

Pharmaceutical technology IV
1.
a) Dosage forms as carrier systems, classification. Routes of
drug administration and technological aspects of effectiveness
Semisolid dosage forms: Ointments, pastes, gels creams,

suppositories, foams
Solid dosage forms compounded by aggregation: powders,
granules, pills, sticks, patch.
- Ointments: Ointments are formulated to provide preparations
that are immiscible, miscible or emulsifiable with the skin
secretion. Hydrophobic ointments and water-emulsifying
ointments are intended to be applied to the skin or certain
mucous membranes for emollient, protective, therapeutic or
prophylactic purposes where a degree of occlusion is desired.
Hydrophilic ointments are miscible with the skin secretion
and are less emollient as a consequence.
- Creams: reserved for external preparations. Creams are
viscous semisolid emulsions for external use. Medicaments
can be dissolved or suspended in creams. A cream may be
‘water-in-oil’ or ‘oil-in-water’ depending on the emulsifying
agent used. A cream is always miscible with its continuous
phase.
- Pastes: Pastes are semi-solid preparations for external use.
They consist finely powdered medicaments combined with
powder多 White Soft Paraffin or Liquid Paraffin or with a non-greasy
base made from glycerol, mucilages or soaps. Pastes contain a
localeffect
high proportion of powdered ingredients and therefore are
normally very stiff. Because pastes are stiff they do not
spread easily and therefore this localises drug delivery.
- Gels: Pharmaceutical gels are often simple phase, transparent
semi-solid systems that are being increasingly used as
pharmaceutical topical formulations. The liquid phase of the
gel may be retained within a 3D-dimensional polymer
matrix. Drugs can be suspended in the matrix or dissolved in
the liquid phase.
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- Poultices: Poultices consist of a hydrophilic heat-retentive
basis in which solid or liquid active substances are dispersed.
They are usually spread thickly on a suitable dressing and
heated before application to the skin.
- Suppositories: solid, single-dose preparations. The shape,
volume and consistency of suppositories are suitable for rectal
administration. They contain one or more active substances
dispersed or dissolved in a suitable basis which may be
soluble or dispersible in water or may melt at body
temperature. Excipients such as diluents, adsorbents, surface-
active agents, lubricants, antimicrobial preservatives and
colouring matter, authorised by the competent authority, may
be added if necessary.
- Semisolid ear preparations: Semi-solid eye preparations are
sterile ointments, creams or gels intended for application to
the conjunctiva or to the eyelids. They contain one or more
active substances dissolved or dispersed in a suitable basis.
They have a homogeneous appearance.
b) Significance of surface active agents, tests:
In a drug the liquid must be able to moisten the solid surface, and
has to be able to enter into the pores of the agglomerates of primer
particles, forcing the air out in order to form the solid-liquid
interface.
Moistening capability can be changed with the addition of surface
active materials.
The tensid may adsorb on the liquid/gas or Solid/liquid interface
decreasing the interfacial tension.
Surfactants may act as :

• Detergents
• wetting agents
• emulsifiers
• foaming agents
• dispersant
Surfactants are usually organic compounds that are amphiphilic,

meaning they contain the hydrophilic group (head) and lipophilic

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part (body).
Surfactants will diffuse in water and adsorb at interfaces between
water and oil.
Into the bulk aqueous phase, they form micelles (simple or
bilayers), the shape of that depends on the balance between
hydrophilic and hydrophobic parts : HLB value.
The dynamics of surfactant adsorption is of great importance for
practical applications such as in foaming, emulsifying or coating
processes, where bubbles or drops are rapidly generated and need
to be stabilized.
In Pharmacy
A wetting agent is a surfactant that, when dissolved in water,
lowers the advancing contact angle, aids in displacing an air phase
air liquid at the surface, and replaces it with a liquid phase. Examples of
application of wetting to pharmacy and medicine include the
displacement of air from the surface of sulfur, charcoal, and other
powders for the purpose of dispersing these drugs in liquid
vehicles; the displacement of air from the matrix of cotton pads
and bandages so that medicinal solutions can be absorbed for
application to various body areas; the displacement of dirt and
debris by the use of detergents in the washing of wounds; and the
application of medicinal lotions and sprays to surface of skin and
mucous membranes measureinterfacialtension
to
rotatinghorizontaltubecontainsdensefluid
fg
Physical tests adropoflessdenseliquidlgasbubbleis
placed
Interfacial and surface tension can be characterized fluid
insidetheby classical
methods such as Spinning-drop Method. Dynamic surface
tensions, i.e. surface tension as a function of time, can be obtained
by the Maximum bubbles Apparatus. maximum tension
pressuremethod measuresurface
bubble
Surface Reology can be characterized by the oscillating drop
method
shear surface rheometers (such as double-cone, double-ring or
magnetic rod shear surface rheometer).
Classification
Most commonly, surfactants are classified according to polar head
group.
A non-ionic surfactant has no charged groups in its head. polysorbae
The head of an ionic surfactant carries a net positive, or negative
charge.
If the charge is negative → anionic (Sodium Lauryl sulfate)

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If the charge is positive → cationic. (secondary or tertiary amines)
If contains a head with two oppositely charged groups →
zwitterionic.
2.
a) Types of drug release. Modified release formulations:
- Conventional-release dosage forms: Are preparations showing a release of active substances

which is not deliberately modified by a special formulation design and/or manufacturing
method. In the case of a solid disage form, the dissolution profile of the active substance
depends essentially on its intrinsic properties. Equivalent term: immediate-release dosage
forms.
- Modified-release dosage forms: preparatiosn where the rate and/or place of release of the
active substances is different from that of a conventional-release dosage form administered
by the same route. This deliberate modification is achieved by a special formulation design
overpeak and/ or manufacturing method. Modified-release dorsage forms include prologed-release,
essfluctuationin delayed-release and pulsatile-release dosage forms.
plasmalevel o Prologed-release dosage forms: showing slower release of the AS than that od a
ere
lessSE conventional-release dosage form administered by the same route. Is achieved by a
special formulation design and/or manufactoring method.
morepatientcompliance
o Delayed-release dosage forms: showing a release of the AS which is delayed. Is
achieved by a special formulation design and/or manufactoring method. Include
gastro-resistant preparations.
o Pulsatile-release dosage forms: showing a sequential release of the AS. Is achieved by
a special formulation design/or manufacturing method.
b) Study of filtration process:

are Tests on packagingmaterialsHydro lyticresistance
Filtration is a technique used either to remove impurities from an
organic solution or to isolate an organic solid. The two types of
filtration commonly used in organic chemistry laboratories are
gravity filtration and vacuum or suction filtration.
S-L separation is a major unit operation that exists in almost every flowscheme related to the
chemical process industries, or beneficiation, pharmaceutics, food or water and wate treatment. The
separation techniques are very diverse.
- Gravity
filtration: is the method of choice to remove solid impurities from an organic liquid.
Can be used to collect solid product, although generally vacuum filtration is used for this
purpose because it is faster. A filtration product called “hot gravity filtration” is used to

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separate insoluble impurities from a hot solution. Require fluted filter paper and careful
attention to the procedure to keep the apparatus warm but covered so that solvent does not
evaporate.
- Vacuum filtration: used primarily to collect a desired solid, the collection of crystals in a
recrystallization procedure. Uses either a Buchner or a Hirsch funnel. Is faster than gravity
filtration, because the solvento r solution and air is force through the filter paper by the
application of reduce pressure. The reduced pressure requires that they be carried out in
special equipment.
Filter materials: paper filters, filter cloth woven cloth, woven wire mesh, monofilament filters (
polyesters, polyprylene, polyamide), cotton canvas, sintered glasss.
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3.
a) Pharmaceutical development, preformulation and formulations:
Requirements for pharmaceutical preparations:

- Quality: including the conditions of manufacture (is known
and defined)
- Efficacy: Except in cases defined in separate regulations (is
clinically proven)
- Relative harmlessness is proven
Among manufacturing industries, the pharmaceutical industry is
the most significantly dependent upon the state of legal and
regulatory measures and the practices of governments, from
clinical development and patenting to regulatory approval,
promoting, and postmarketing surveillance.
The industry faces many challenges today: demands by regulatory
authorities, challenges to intellectual property, competition,
counterfeit medicines, price controls. The purpose of
pharmaceutical technology is to produce drug products (DCS)
which are adequate, safely usable and efficient by therapeutic
considerations. In order to achieve this: special excipients and
dosage forms are needed, out of which good quality products can
be prepared with adequate technological processes.
Adosage form includes: chemical characteristics of the AI,
physical state, extent of its stability, applied excipients, and the
operation parameters of the applied technology.

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Factors effecting the development of industrial drug
manufacturing: Reformulation phaseofresearch development
- Medicinal science (continuously) physicallchemicalproperties
ofdrugstudied inorderto
- Natural materials (til 1880) developsafeeffectiveand
stabledosageform
- Organic chemistry (1880-1935)
Formulation multistepprocesswhereactive
- Pharmacotherapy and R&D (since 1950) drugismixedwith all other
componentsbyconsidering
- Biosynthesis (since 1943) particlesize polymorphism
and becomes
- Equipment development (since the end of 19 century) pHsolubilityth
medicinalproduct
- Industrial drug formulation (1950)
- Analytical test methods ( continuously)
- Authority quality guidance (1950)
- Computers and automation (1970)
Most important tasks of pharmaceutical technology:
- Investigation of the chemical, physic-chemical and physical
characteristics of the AI
- Selection of adequate excipients
- Development of methods, determination of process parameters
- Research and enhacement of stability
- Optimation of biological availability and the control of drug
release
Test ofointmentandsuppositorybasematerials Itestrateofabsorption

2 estofnonirritant
b) Key person, ㅡㅡ
qualified person:
3lestofrateofpenetration
Manufacturer means any person who designs, manufactures,
fabricates, assembles, or processes a finished device.
Manufacturer includes but is not limited to those who perform the
functions of contract sterilization, installation, relabeling,
remanufacturing, repacking, or specification development, and
initial distributors of foreign entities performing these function
Qualified Person (QP) is a technical term used in European Union
pharmaceutical regulation. The regulations specify that no batch

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tests description identificationassay
universal
impurities
of medicinal product can be released for specific testspH
sale or supply prior to viscosity
apparent uniformity
ofdosageunit
certification by a QP that the batch is in accordance with the watercontent
relevant requirements. microbiallimit
particlesize
preservative
The QP is typically a licensed pharmacist, biologist or chemist (or effect
a person with another permitted academic qualification) who has
several years experience working in pharmaceutical
manufacturing operations, and has passed examinations attesting
to his or her knowledge. In countries that are part of the
Pharmaceutical Inspection Convention and Pharmaceutical
Inspection Co-operation Scheme (PIC/S), the same role may be
termed Responsible Person (RP) or Authorized Person (AP).
4.
a)Stability of drugs and medicinal preparations. Unwanted
changes and expirations:
To provide evidence how the drug substance or drug product

quality changes over time due to various environmental
influences, such as temperature, humidity and light, and To
determine in the case of drug substance the time of „recontrol”, in
the case of drug the shelf life, and To determine the „ideal”
storage conditions.
Stability test:
Series of experiment in which information obtained about the
stability of drug in order to determine storage time and shelf life
under the given packaging and storage conditions.
- Real time stability studies: Series of experiments to study the
physical, chemical, biological, biopharmaceutical and
microbiological properties of drugs during and after the shelf
life under expected storage conditions. The results are use the
determine the shelf life and the storage conditions and to
prove the correctness of planned shelf life.
- Accelerated stability tests: The changes during extreme
storage conditions occurs faster. The data obtained this way
together with real time stability studies can be used to
determine the long term changes. It also can be used to

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determine what happens in short term extreme conditions
(e.g. shipping). t
accuracy
General conditions during stability tests: study of photostability,
selection of batches, packaging.
Stability and preformulation: in the early drug development phase
chemical and physico-chemical properties of substances should be
determined:
- Study of physical, chemical properties of substances
- Study of drug stability
- Compatibility study of substances with excipients necessary
for formulation
Degradation specific studies: selective and sensitive determination
of drug in the presence of degradation or reaction products. The
suitable methods are spectrophotometry, gas and liquid
chromatography and couple techniques.
During the stability tests the preparation must be controlled
regularly and fully using physical, chemical biological and
microbiological examinations.
b) Comparison of dry and wet milling processes: inpharmaindustry wetmining후

drying dryminingshowsmore
Wet milling is a larger, more versatile process, and can be valuable uniformsizeand
for dealing with volatile markets. Wet milling can be used to lessproportionof
produce a greater variety of products such as starch, corn syrup, fineswhichalter
ethanol, and Splenda to name a few. Although wet milling is a theamountof Api
weightIrobustness
more versatile process and produces more products than dry dissolutionprofile
milling, when producing ethanol, dry milling has a higher Alsoreduceddrying
efficiency and lower capital and operating costs. For this reason, timereducedthermal
most of the ethanol plants within the U.S. are dry milling exposureofAPl
operations
5.
a) Significance of compatibility. Physical and chemical
incompatibilities in pharmaceutical technology:
Types of drug interactions:
- Pharmacokinetic Drug Interaction intake milk
grapefruitjuicefood 여
CYPinducerIinhibitor

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- Alteration of Gastrointestestinal Absorption
- Alteration of Distribution 
- Stimulation of Metabolism 
- Inhibition of Metabolism 
- Alteration of Excretion
Pharmacodynamic Interaction
- Drugs Having Opposing Pharmacological Effects
- Drugs Having Similar Pharmacological Effects
- Alteration of Electrolyte Concentration
一一
- Interaction at Receptor Sites
Pharmaceutical interaction
 a) wanted=used as formulation technology
b) unwanted=incompatibilityà Physical Incompatibility, Chemical
Incompatibility, Therapeutic Incompatibility
Incompatibility may be Chemical, Pharmaceutical or
Therapeutical, according as the incompatible combination results
in chemical decomposition, physical disassociation, or
antagonistic physiological action.
 Disadvantage: scrupulous therapeutical application
 - decrease of efficacy, lack od proper dosing 
- decrease of safety (increased toxicity), lack od proper dosing
The quality of not being miscible with another given substance
without a physical or chemical change. One drug is not of suitable
composition to be combined or mixed with another agent or
substance. The incompatibility usually results in an undesirable
reaction, and disturbs the quality, safety and efficacy of the drug
preparation.
These interactions occur prior to systemic administration. For
example incompatibility between two drugs mixed in an IV fluid.
These interactions can be physical (e.g. with a visible precipitate)
or chemical with no visible sign of a problem

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Physical:
Physical incompatibilities are often called pharmaceutical
incompatibilities and are evidenced by the failure of the drugs to
combine properly. It is virtually impossible for uniform dosages of
medicine to be given from such solutions or mixtures. Ingredients
ppt such as oil and water, which are physically repellant to each other,
Xuniform and substances that are insoluble in the prescribed vehicle are
primary examples of physical incompatibilities.
Chemical:
This type of incompatibility exists when agents are prescribed that
react chemically when mixed, altering the composition of one or
more of the constituents. The Dangers of Incompatibility may in a
great measure be avoided by the use of the utmost simplicity in
prescribing. The subject can only be glanced at within these pages,
but the following simple rules may help the burdened memory of
the student and the practitioner.
b) Study of homogenization:
High pressure homogenization: High-pressure homogenization is
based on the principle of cavitation (i.e., the formation, growth,
and implosive collapse of vapor bubbles in a liquid. In this process,
a drug presuspension (containing drug in the micrometer range) is
prepared by subjecting the drug to air jet milling in the presence of
an aqueous surfactant solution. The presuspension is subjected to
high-pressure homogenization in which it passes a very small 
homogenizer gap of ~25 um. Cavitation forces are created, which
are sufficiently high to disintegrate drug microparticles to
nanoparticles as the suspension leaves the gap and normal air
pressure is reached again. The homogenization pressure and 100 1500 bar
number of homogenization cycles are key parameters in
3.3.10
optimizing the process. The homogenization pressures generally
range from 100 to 1500 bar and the number of homogenization
cycles could be 3, 5, or 10 depending upon the drug's hardness,
the desired mean particle size, and the product's required
homogeneity
6.
a) Packaing technology and packaging materials

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Main function of packaging: Making units (for dose/therapy), makingunits
improve compliance Protection Identification/appearance (color, protection
shape, label) Grouping, collecting identification
appearance
Tamper evidence/proof, childproof Information (PIL=Patient
Information Leaflet)
Demands: Protection (stability test conditions), compatibility,

regulatory, legislation, comercial (image, market requirements,
dosing/patient compliance, security/tamper evidence,
manufacturing, economics).
Container: A container for pharmaceutical use is an article which
contains or is intended to contain a product and is, or may be, in
direct contact with it. The closure is a part of the container. The
container is so designed that the contents may be removed in a
manner appropriate to the intended use of the preparation. It
provides a varying degree of protection depending on the nature of
the product and the hazards of the environment, and minimises the
loss of constituents. The container does not interact physically or
chemically with the contents in a way that alters their quality
beyond the limits tolerated by official requirements.
Single dose container: holds a quantity of the preparation intended primary direct
for total or partial usea as a single administration contactWIAPI
secondary notdirect
Multiple container: holds a quantity of the preparation suitable for contact
WIAPI
two or more doses.
Well-closed container. A well-closed container protects the
protectfromcontaminant
contents from contamination with extraneous solids and liquids
preventloss ofcontents
and from loss of contents under ordinary conditions of handling,
storage and transport.
Airtight container. An airtight container is impermeable to solids,
liquids and gases under ordinary conditions of handling, storage
and transport. If the container is intended to be opened on more
than one occasion, it must be so designed that it remains airtight
after re- closure.
Sealed container. A sealed container is a container closed by
fusion of the material of the container. 
Tamper-proof container. A tamper-proof container is a closed

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container fitted with a device that reveals irreversibly whether the
container has been opened.
Child-proof container. A container that is fitted with a closure that
prevents opening by children.
Packaging materials: primary PM: which are in direct contact with
the phaarmaceutical preparation. Secondary PM: which are not in
direct contat to the pharmaceutical preparation
Packaging material must:
- Have protection against counterfeit products
- Tamper resistant
- Rings
- Seals powder mixtureof finelydividedmaterialslchemicals
drugs in a dryform
- Childproof granules agglomerates of powder material in large
- Braille information free flowingparticles or small compact
particle of a substance
b) Characterization of powders and granules:
Granules: betterflowabilitythan powders easierto compress intotablets
- Particle size and shape: size affects the average weight of morestable in
Tablet, DT, friability, flowability and drying rate. Methods toatmosphericcondition
determine: sieving, sedimentation rate, micrscopy, by light likelightmoisture
temperatureI
scattering.
Canbeformulated
- Surface area: not commonly used for granules as sustainedrelease
- Density: may influence compressability, Tablet porosity and
dissolution, dense hard granules may require higher load to
produce cohesive compact to reduce free granules seen on
the surface of tablets.
- Strenght and friability are measured wiht the compressive
strengh and using friability measurements.
- Moisture content
Powders: canbeappliedexternally on skin 0.1 10microns causes dust bIN
- Particle size: can be determined by different methods: sieve handling
analysis, image analysis laser analysis etc

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- Particle shape: can be calculated by ellipticity, roundness,
angularity,
- Flowability: is the result of the combination of material
physical properties that affect material flow and the
equipment used for handling, storing, or processing the
material.
- Surface area: a number of methods can be used to determine it
: coulter counter, stoke’s law, light scattering, permeametric
methods, sieving, SEM, TEM
7.
a) Basics of chemical engineering, critical manufacturing
parameters and scaling up. Unit operations:
Significant factors at determining the input and output of
materials:
- Chemical composition
- Physical state
- Distribution of materials
- Temperatura
- pH
- pressure
Chemical engineering deals with the application of physical
science and life science with mathematics. To the process of
converting raw material sor chemicals into more useful or
valuable forms. In addition to producing useful materials, modern
chemical engineering is also concerned with pioneering valuable
new materials and techniques.
Process engineering largely involves the design, imporvement and
maintenance of processes involving chemical or biological
transformations for large-scale manufacture.
Unit operations: In chemical engineering and related fields, a unit
operation is a basic step in a process. An overall chemical process
is commonly made up of steps called unit operations. Each unit
operations may be connected to build up the overall process. A
process may have many unit operations to obtain the desired

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product. Consists of 5 classes:
- Fluid flow processes, including fluids transportation, filtration,
solids fluidization
- Heat transfer processes, including evaporation, condensation  
- Mass transfer processes, including gas absorption, distillation,
 extraction, adsorption, drying
- Thermodynamic processes, including gas liquefaction,
refrigeration
- Mechanical processes, including solids transportation,
crushing and pulverization, screening and sieving
Basic laws of chemical engineering:
Number of parameters
Scale Up
Effect of autimatization
Costs
Critical manufacturing paramenter is a process paramenter that

must be maintained within prescribed limits to achieve the desired
quality outcome (critical quality attributes). Physical, chemical,
biological, or microbiological property or characteristic that
should be within an appropriate limit, range, or distribution to
ensure the desired product quality.  CQAs are generally associated
with the API(s), excipients, intermediates, and drug product.
CQAs include the properties that impart the desired quality, safety,
and efficacy.  CQAs of solid oral dosage forms are typically those
aspects affecting product purity, potency, stability, and drug
release.
Comon critical manufacturing parameters:
Product quality: active ingredient content, purity, chemical,
microbiological, drug release profile
Production: community pharmacies, industrial production
(production of actives, production of medicinal products)
A process parameter whose variability has an impact on a CQA

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and therefore should be monitored or controlled to ensure the
process produces the desired quality.
Scale up: Act of using results obtained from laboratory studies for laboratory
designing a protototype and pilot plant process, construction a d
pilot plant to adapt large industrial scale. Is important ar: prototypel
- Dynamic processes (transport and transfer powders, liquids, pilotplant
gas and mixing , dissolution, homogenization) t
largeindustrial
- Thermal processes (heating, cooling, melting, freezing) scale
- Diffusion type processes (drying, evaporation, distillation)
- Mechanical processes (size reduction, grinding- milling,
tabletting)
The factors that influence the scaling up are physical parameters
of the AI and auxiliary materials, intermediers, dependence on
apparatus and quipment, dependence of quantity.
Similarity studies in scale up:
- 4 dimensions – force, mass, distance, length Lack of differential
equations during pilot trials limits usefullness
- Dynamic – equality between dimensionless numbers. Not always
possible to achied dynamic simirarity between scales. Differences
such as vortexing and surface tension can effect results
- Chemical – often impossible to determining rate limiting
reactions in system. Diffusion and temperature can be important
and not always comparable at different scales
Problems: there is usially a lack of data of physical properties for
complex formulation( specific heat cpaacities, termal
conductivies, phase relationship, rheology)
b) Testing and evaluation dissolution:
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
The main objective of developing and evaluating an IVIVC is to establish the dissolution test as a
surrogate for human studies, as stated by the Food and Drug Administration (FDA). Analytical data
from drug dissolution testing are sufficient in many cases to establish safety and efficacy of a drug
product without in vivo tests, following minor formulation and manufacturing changes. Thus, the
dissolution testing which is conducted in dissolution apparatus must be able to provide accurate and
reproducible results.

Page 15 of 67
8.
a) Physicochemical and rheological principles of pharmaceutical technology. Test methods:
Rheology is the study of flow behaviors of liquids. In pharmacy,

there are many liquid and semi-solid formulations such as
ointments, lotions, suspensions, emulsions, syrups, etc. where the
knowledge of flow behavior is essential for optimum formulation
design. In preparing an ointment, for instance, you need to be
concerned about its ability to be spread on the skin or eye surface.
The solid drug particles in suspensions should not settle readily,
otherwise the patient will not receive the correct dose each time.
In general, the flow properties of pharmaceutical liquids and semi-
solids are important for:
1. Preparation of products. Whether on small scale
(extemporenous compounding) or in industry, the knowledge of
flow behavior is essential during formulation.
2. Stability of suspensions and emulsions. Suspension particles
will settle very quickly in less viscous liquid medium (Stokes
law). The oil phase of the emulsion will rapidly coalesce if the
viscosity is not at its optimum.
3. Pouring liquid and semi-solid medications in and out of the
container. 4. Spreading the product on the skin or the eye.
Pharmaceutically-relevant liquids and semi-solids fall under the
two important rheological profiles - Newtonian and non-
Newtonian rheological behaviors.
A. Newtonian Rheology:
The flow behavior of some liquids like water, alcohol, glycerin,
syrup, etc. fall under the category of Newtonian rheology. In this
case, when a force is applied to the liquid of a given surface area,
the liquid immediately begins to flow. As the force per area is
increased, the velocity of flow increases proportionately. In
rheology, the force per unit area is called shear stress and the
velocity of flow is rate of shear. Mathematically, the relationship 뺏은晳毖 낦썐
is expressed as follows.
The shear stress, τ, between layers is proportional to the velocity
gradient, ∂u/∂y,
Force/Area = (constant)(Velocity of Flow) or F/A = η(dv/dr)
The proportionality constant is called viscosity (η) of Newtonian

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fluid. The unit of viscosity is a Poise. However, for most
Newtonian liquids of pharmaceutical interest, the viscosity is low
enough for us to use centiPoise (cps or 1/100 Poise).
One of the method of measuring Newtonian visocity is with an

Ostwald viscometer. This is a U-shaped glass tube containing a
very thin bore that allows the liquid of interest to flow slowly
from one end to the other. The time taken for the liquid of interest
to flow in the Ostwald viscometer from point A to B is compared
with the time for a standard liquid with known viscosity (e.g., pure
water).
The viscosities of the two liquids are then related to the time of
flow and their densities as follows:
(η1/η2) = (t1 ρ1)/(t2 ρ2)
B. Non-Newtonian Rheology:
Lotions and ointments, for instance, will not spread easily on the
skin until a certain additional force is applied in the form of
rubbing. The flow behavior of ointments, suspensions, polymer
solutions and syrups fall under the category of non- Newtonian
rheology. There are three different types of non-Newtonian
rheograms.
1. Plastic Rheogram: is very similar to Newtonian rheology,
except the liquid does not begin to flow until a certain finite shear
stress called the yield value is applied. The knowledge of yield
value is important since suspensions will not flow out of their
container until the bottle is shaken several times so that the stress
exceeds the yield value. Similarly, many other pharmaceutical
products have a specific yield value before they begin to flow. The
slope of the linear portion of the plastic rheogram gives the
reciprocal of plastic viscosity or is equal to plastic fluidity.
2. Pseudoplatic Rheogram: The second type of non-Newtonian
flow behavior is non-linear. The flow begins immediately when
the stress is applied, however, the viscosity of the liquid decreases
with increasing shear stress. This type of flow behavior is called
shear thinning. Many water-soluble proteins and polymer
solutions (e.g., albumin, gelatin) or when polymers are added to

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pharmaceutical products (e.g., in suspension formulation), they
exhibit pseudoplastic flow.
3. Dilatant Rheogram: The last non-Newtonian flow behavior is

called dilatant flow. As in the case of pseudolastic flow, in dilatant
systems the flow begins immediately when the stress is applied.
As the stress is continually applies, however, the viscocity of the
liquid increases. This type of liquids (e.g., suspensions with a
solid content of more than 50%) are called shear thickening.
b) Test of membrane filters:

Filter media: produced from pure cellulose, cellulose derivatives
and polymeric materials. Have an extremely uniform micropore
structure, and an exceptionally smooth surface. The integral
structure: no fibers or particles which can work loose and
contaminate filtrate; advantage in the filtration of ophthalmic
solutions -> the presence of fibers is difficult to prevent when
using many other filter media, including paper filters
The efficiency: due to the uniform pore system -> functions like a
highly effective sieve.
Pore size range: from 10 nm to 10 µm. All larger particles in
liquids or gases are retained on the surface.
Thickness: 50-200 µm; the pores pass directly through the entire
thickness of the membrane, with a minimum of cross-linking.
Porosity or pore volume: ~80% of the total volume. The high
porosity and the “straight-through” configuration gives flow rates
at least 40 times faster than through conventional filters with the
same particle size retention capabilities.
Small volumes (>500 ml): usually filtered using vacuum
techniques; larger volumes: filtration under pressure, by an inert
gas (nitrogen)
Used both in lab and industrial scale. Wide range of uses:
chemical analysis, microbiological analysis, bacterial filtration ->
economical and rapid method for sterilizing heat-labile material.
Non-destructive integrity test:
• Bubble point test: wetting the membrane makes it impermeable
to gas underneath; a gas pressure displaces the liquid from the
filter; the pressure at which bubbles start to appear on the
underside of the filter is the bubble point:

Page 18 of 67
p = ((4σ Cosβ)/r)K
σ = surface tension of wetting fluid,
β = wetting angle, r = pore radius,
K = correction factor
Determination should be carried out before and after filtration
Pressure drop/holding test: the basis of the determination is the
effectiveness of holding a pressure applied on the closed inert side
of the system
PA - Pv = (VD t p0)/VG
VD = gas diffusion,
t = test time,
p0 = atmospheric pressure,
VG = volume of inlet part
• Diffusion test: a quantitative measurement of air/gas diffusion
through the membrane at a pressure below the rated bubble point
of the finest filter
N = D L (Δp/d) F
N = number of molecules/sec,
D = diffusion coefficient,
L = gas solubility coefficient,
Δp = pressure difference,
d = thickness of liquid film on the membrane,
F = effective area of filtration
9.
a) Particle size reduction (milling). Particle size
measurements:
The metrical size of the solido r liquid particle in the dispersing
phase. The particle size distribution (%) expressed as numbers,
mass, volumen of the fractions in a given size range.
Many methods are available to measure sizes and size
distributions of particles and droplets: sieving, sedimetnation,
electrozine and photozine sensing, image analysis, laser
diffraction, photon correlation spectroscopy.
Small drug can be prepared either by a mechanical size reduction
or alternatively by a controlled drug particle engineering
technique.
1. particle size reduction (top down): comminution of previusly

Page 19 of 67
formed larger particle using milling processes such as jet
milling, Pearl-ball milling, or high pressure homogenization.
2. Particle engineering (bottom up): by integration under
controlled from molecularly dispersed drug.
Common reasons for reducing partcile size:
- Create appropiare particle size for subsecuent procesisng or
end use
- Create a free-flowing material
- Improve material blending and prevent segregation by making
different sized products with similar particle size
distributions
- Increase the materials surface area to imporve a materials
reactiveness, dissolution or drying efficacy
- Control a materials bulk density by creating a particle isze
distribution consisting of a matrix of larger particles with
smaller particles filling voids between the larger particles.
Understanding size reduction forces: to reduce a materials particle
size, large particles or lumps must be fractured into smaller
particles. To initiate fractures, external forces are applied to the
particles. When a solid particle is subjected to a mechanical stress
that excedes its strength, cracking is initiated. As a cracks are
propagated, stored strain energy is released leading eventually to
massive fracture of the particle. At lower stress level, especially
for particle of irregular shape, the strengh of the material may be
exceded locally, giving rise to more limited breakage at edges or
corners.
Generally, the amount of particle reduction caused by an external
force depends on the amount of energy applied to the particle, the
rate at which its applied, and the manner in which its applied.
Degree of size reduction: A= Xo/Xf. Energy is required (in the
equation the energy is proportional to reduction in size)
b) Isotinizing setting and calculations:

This method has the advantage that for a new active ingredient or adjuvant, whose osmotic pressure
in solution is still unknown, one can calculate the amount of NaCl required to adjust isotonicity, at
least with appropriate accuracy.

Page 20 of 67
For the calculation, the type of the dissociation must be known, which requires the determination of
the molal freezing point depression:
L = ΔT/c,
L - molal freezing point depression of the solute

ΔT - freezing point depression of the solution of injection
c - molar concentration of the solution
The term “NaCl equivalent” (ENaCl) means the quantity of salt that will produce osmotic pressure in
the solution which is equal to the osmotic pressure produced by 1g of the active ingredient in
question.
The compounds have been grouped according to their L-values.

The E value is calculated:
E = (L×MNaCl)/(M×LNaCl) = (L×58×45)/(M×3×4) = 17 (L/M)
M - molecular mass of the compound

In practice, the application of the NaCl equivalent in the followings:
• the given quantities of the compounds are multiplied by their E-value
• The Na equivalent of the compounds are added up
• The resulting value is subtracted from the amount of NaCl that would be required to make the
solution isotonic
• If isotonicity is to be adjusted by some other additive, e.g. Dextrose, then the calculated deficiency
of NaCl is divided by the E-value of dextrose.
10.
a) Preparations prepared by extraction. Principles and
methods:
Removal of soluble materials from an insoluble residue. Infusión:
the weighed quantity of drug is kept in contact with known
wuantity of menstrum for a specific period of time.
Decoction: drug is boiled with the menstrum for a specified period
of time
Maceration: solid materials with whole of menstrum in a closed
vessel and allowed to stand for 6 days shaking occasionally and
mix the liquid obtained with the mother liquor and clarify the
filtration. Digestión is a form of maceration in which gente heat is
used during the process of extraction. It is used when moderately
elevated temperatura is nor objectionable. The solvent efficiency
of the menstruum is thereby increased.
Sonication-assited extraction: Sound waves, which have
frequencies higher than 20 kHz, are mechanical vibrations in a
solid, liquid and gas. Is an inexpensive, simple and efficient
alternative to conventional extraction techniques. The main

Page 21 of 67
benefits of use of ultrasound in solid–liquid extraction include the
increase of extraction yield and faster kinetics. Ultrasound can
also reduce the operating temperature allowing the extraction of
thermolabile compounds.
Microwave-assited extraction: Microwaves are electromagnetic
radiations with a frequency from 0.3 to 300 GHz. Microwaves are
transmitted as waves, which can penetrate biomaterials and
interact with polar molecules such as water in the biomaterials to
create heat. Consequently, microwaves can heat a whole material
to penetration depth simultaneously. Water within the plant matrix
absorbs microwave energy, cell disruption is promoted by internal
superheating, which facilitates desorption of chemicals from the
matrix. The chosen solvent should possess a high dielectric
constant and strongly absorb microwave energy. Solvents such as
ethanol, methanol and water are sufficiently polar to be heated by
microwave energy. Non-polar solvents with low dielectric
constants such as hexane and toluene are not potential solvents for
microwave-assisted extraction.
Percolation: This is the procedure used most frequently to extract
active ingredients in the preparation of tinctures and fluid extracts.
A percolator (a narrow, cone-shaped vessel open at both ends) is
generally used. The solid ingredients are moistened with an
appropriate amount of the specified menstruum and allowed to
stand for approximately 4 h in a well-closed container, after which
the mass is packed and the top of the percolator is closed.
Additional menstruum is added to form a shallow layer above the
mass, and the mixture is allowed to macerate in the closed
percolator for 24 h. The outlet of the percolator then is opened and
the liquid contained therein is allowed to drip slowly. Additional
menstruum is added as required, until the percolate measures
about three-quarters of the required volume of the finished
product.
b) Innovate and generic products:
Patientcentricity
1. Development and registration of new original drugs: research of
new drug action mechanism, decreasing of side effects, achieving
of new therapeutic possibilities (improvement of quality of life,
widespread disease, incurable disease, development of new
dosage forms). The composition procedure from the AI should be:
suitable for/proper to the therapeutic requirements, safely

Page 22 of 67
applicable, effective)
2. Registration of new generic drug product: development of
classic generic products, generic plus (development of generic
(retarde) products (having the originals PK), development of new
type pharmaceutical techonological dosage forms
3. Modernization, cost reduction of available procedures:
manufacturing of AI (new produces, higher yied, less steps of
synthesis), composition (reformulation, up to date excipients, up
to date packaging materials), cost reduction.
Basic concepts:
- Discovery: disclosure and bringing into notoriety of a matter
or phenomenon not yet known to science
- Invention: prepairing/ framing or working out a procedure,
tool or technological solution for the first time
- Patent: is an exclusive right granted for the invention, by right
of which the invention can be utilized by the entitled.
Everyone else is prohibited from utilization. Extent: 20 years
types: primary: product patent, procedure , equipment and
application patent. Secondary: new pharmacological
indication,
-
pharmacologically active metabolites, 一一
polimorphism, new formulations, procedure in
pharmaceutical technology.
Patent oopportunities in generic development: bypass synthesis
ways, pharmaceutical technological formulation, composition of
original PK
Pharmaceutical equivalence: Medicinal products are

pharmaceutically equivalent if they contain the same amount of
the same active substance(s) in the same dosage forms that meet
the same or comparable standards. does not necessarily imply
bioequivalence as differences in the excipients and/or the
manufacturing process can lead to faster or slower dissolution
and/or absorption.
Pharmaceutical alternatives: Medicinal products are
pharmaceutical alternatives if they contain the same active moiety
but differ in chemical form (salt, ester, etc.) of that moiety or in

Page 23 of 67
the dosage form or strength.
Essential similarity: A medicinal product (Test product) is
essentially similar to an original product (Reference product)
where it satisfies the criteria of having the same qualitative and
quantitative composition in terms of active substances, of having
the same pharmaceutical form, and of being bioequivalent unless
it is apparent in the light of scientific knowledge that it differs
from the original product as regards safety and efficacy.
11.
a) Drying process, spray drying, freeze drying:
Drying: removal of a liquid from a solid by evaporations. Is a
process in which volatile liquid, usually water, is removed from a
solid material by evaporation. During drying , the following two
processes occur: heat-transfer and mass-transfer
Drying rate influencing factors: Because dryer performance is
measured by its ability to remove water from a product,
measurement of the product mass flow and moisture content into
the dryer is important in performance assessment. Bulk density
and particle density will influence the resistance to airflow and the
diffusion of water internally. The size of the individual particles
also will influence the drying rate because internal diffusion will
become a rate-limiting factor for large particles (>10 mm). The
temperature of the incoming product will affect dryer performance
because part of the energy input to the drying process may be
required to heat the product before drying can begin.
Factors influencing the drying process:
- Vapour pressure and relative
- Temperature
- Air movement
- Supply of heat
- Movement of moisture in the solid material
Spray drying:
Spray Drying is a unique method to convert a solution, suspension
or emulsion into a solid powder in one single process step. It is a

Page 24 of 67
widely established process in many industries such as
pharmaceuticals, food, chemical or material science.  Atomization
of a solution of one or more solids via a nozzle, spinning disk, or
other device, followed by evaporation of the solvent from the
droplets is termed spray-drying.
A special kind of drying process in which solutions or liquid
dispersions are carried in form of fine droplets mostly into hot air
or gas flow where the liquid material evaporated quickly resulted
solid products.
Advantages:
1. Applicable on drying of sensitive (heat, oxygen) materials as
vitamines, hormones, antibiotics, vegetable extracts; 
advantageous modification of physical properties (shape,
size, amoprhous forms, flowability etc.) of intermediate
products in tabletting or capsule filling; Embedding of solids
or liquids (microencapsulation); Get low energy surface
containing particles; avoid incompatibilities
2. Useful solution for increase stability (product has a very low
moisture content); 
3. Applicability for optimalization of drug delivery, in
consequence of the extremely large inner surface
advantageous the absorption ( better wettability, higher
dissolution rate). 
4. The process is quick, continuous, indulgent; automatizable.
Does not appear local heating, which can be observed in
micronization process.
The nature of the powder that results is a function of several
variables, including the initial solute concentration, size
distribution of droplets produced, and rate of solvent removal. The
particles produced are aggregates of primary particles consisting
of crystals and/or amorphous solids, depending on the rate and
conditions of solvent removal. This approach to the powdered
state provides the opportunity to incorporate multiple solid
substances into individual particles at a fixed composition,
independent of particle size, and avoiding difficulties that can
arise in attempting to obtain a uniform mixture of several
powdered ingredients by other procedures.

Page 25 of 67
Process parameters affecting characteristics of product: revolution
number and diameter or atomizing disc, temperatura of drying air,
dosing rate, ratio of drying and liquid, diameter of atomizing
nozzie.
Freeze drying:
The removal of water or other solvent from a frozen material by
sublimation caused
The aspect of the freeze-drying technique that makes it different
from other drying processes is that dehydration takes place while
the material is in a frozen state and under a vacuum. Under these
conditions the stress (heat or oxygen, other degradation effects) is
minimized to stabilize the product. Freeze-drying has become an
accepted method of processing heat sensitive products that require
long-term storage at temperatures above freezing.
Freeze-drying was first actively developed during WWII. Serum
being sent to Europe for medical treatment of the wounded
required refrigeration. Due to the lack of available refrigeration,
many serum supplies were spoiling before reaching the intended
recipients. The freeze-drying process was developed as a
commercial technique that enabled serum to be rendered
chemically stable and viable without having to be refrigerated.
Shortly thereafter, the freeze-dry process was applied to penicillin
and bone, and lyophilization became recognized as an important
scientific technique for preservation of biologicals. Since that
time, freeze-drying has been used as a preservation or processing
technique for a wide variety of products. Some of the applications
include the processing of pharmaceuticals, diagnostic kits,
restoration of water-damaged documents, river bottom sludge
prepared for hydrocarbon analysis, ceramics used in the
semiconductor industry, viral or bactehal cultures, tissues prepared
for analysis, the production of synthetic skins and restoration of
historic/redaimed boat hulls.
Freeze drying is performed in a frozen product in a vacuum below
the triple point, where water can only be present in two phases: ice
and vapor. The ice will be sublimated from the water phase
directly into vapor. For foods, this ensures that the product retains
most of its original shape, color, taste and nutritients. unchanged
Why freeze-dry food?

Page 26 of 67
to completely remove water for preservation (from bacterial
growth, enzyme stabilization, leaving the basic structure and
composition of the material intact. Freeze-drying significantly
reduces the total weight of the food. Removing this water makes
the food a lot lighter, which means it’s easier to transport. The
military and camping supply companies freeze-dry foods to make
them easier for one person to carry.
Process steps are:

- Freezing
- Vacuum
- Heat
- Condensation
Advantages:
1. Fewer stability problems, the product is stored in dry state
2. Good for thermolabile materials, the product is dried without
elevated temperaturas
 3. Good for oxygen and/or air-sensitive drugs 
4. Rapid reconstitution time 
5. Constituents of the dried material remain homogenously
dispersed
 6. Product is process in the liquid form 
7. Sterility of product can be achieved and maintained
Disadvantages:
Higher costs, an expensive unit operation
- Equipment
- energy consumption 

Page 27 of 67
Time consuming (e.g. 12-49 hours) 
The product could be hygroscopic, stability problems associated
with some drugs
 Volatile compounds may be removed by high vacuum
Challenge of sterilization and sterility assurance in chamber and
during aseptic loading of vials
b) GMP documentation:
Good manufacturing practice.
- Document: is a stream of data that, after being combined with
any other streams it references, is structured such that it holds
information contained within elements that are organized as
defined in the associated DTD
- DTD or document type definition, is a collection of
declaration that, as a collection, defines the legal structure,
elements, and attributes that are available for use in a
document that complies to the DTD
12
a) Liquid dosage forms. Dissolving, homogenizing:
Dosage forms are essentially pharmaceutical products in the form
which involves a mixture of actuve drug components and nondrug
components. Liquid form of a dose fo a drug used as a drug or
medication intended for administration or consumption.
They are prepared by:

- Dissolving the active drug substance in an aqueous or non
aqueous solvent
- By suspensinf the drug in apporpiate médium
- By incorporating the drug substance into an O/W phase.
Advantages:
- Better for patients who have troubles swallowing expiration
than other

Page 28 of 67
- Faster absorption than solids
- More flexibility in achievig the proper dosage of medication
- Palatable
- Best choice for children and old age person
Disadvantages:
- Shorter life than other dosage form
- Harder to measure accuracy
- Need special storage condition
- Less stable
- Easily affected by MO
- Bulky to carry around
- Easy to loss by the breakage of the container
- Measuring dose is required
Types:
Syrups, otic preparations, collodion, nasal preparations, aromatic
waters, spirit/esseces, elixir, mouthwash, tinctures, gargles, fluid
extract, astringent, douche, antibacterial, enema, topical solution,
liniment.
b) Testing starting materials: Tablet IPC of tabletting
tingparameters
Raw materials analysis requires a wide range of analytical
chemistry expertise. The most common tests performed in a raw
materials laboratory include titrations, loss on drying, Karl Fischer
moisture determination, heavy metals limit tests, and infrared
spectrophotometry. Full monograph testing often requires as many
as seven different analytical techniques. For example, to perform
full USP Monograph testing for methylparaben, eight different
tests using six analytical techniques ranging from infrared
absorption to gas chromatography are required. Therefore, the
most efficient organization of a raw materials laboratories is by
function so that analysts can specialize in specific techniques. To
perform even basic monograph testing, laboratorios must contain
a wide spectrum of instrumentation. The most commonly
specified instruments include

Page 29 of 67
● pH meters/ion meters
● balances
● gas chromatographs(GCs)
● high-performance liquid chromatographs (HPLCs)
● infrared spectrophotometers
● UV-Visible & Fluorescence spectrophotometers
● Tintometer
● Karl Fischer moisture titrators
● Auto-titrators & titration apparatus
● Vacuum ovens
● Melting-point apparatus
● Thin layer chromatography apparatus(TLC)
● Polarimeter
● Refractometer
● Viscometers
● Muffle furnace To expand the number and variety of excipients
that can be tested, additional instrumentation is required. These
include
● Flame atomic absorption spectrophotometer
● Graphite furnace atomic absorption spectrophotometer
● Osmometer
● Inductively coupled Plasma Spectrometer
● Mass spectrometer
13.
a) Crystallizationg. Importance of polymorphic and
amorphous materials. Characterization of the solid state:
Crystallization:
involves a reversal of the charges which occurs when a solid melts or dissolves.
Typically: regular geometric form with sharp edges and plane surfaces.
The crystalline nature is revealed only by microscopic examination.
Regular assembly of atoms or ions arranged in a space lattice having a uniform geometrical form;
even if the external form is destroyed by powdering, the internal structure remains.
Symmetry: expressed in terms of symmetry around certain planes or axis - crystal can be rotated
o
360 , and occupy the same position more than once.
Classification of crystals:
cubic, triclinic
Polymorphism:
2 or more crystalline forms - difference in crystalline structure - give rice to different physical
properties – allotropy
Enantiotropic: reversible transition between polymorphic forms
Monotropic: irreversible, transition from metastable to stable form, unidirectionally.
Detection of different polymorphic forms: by X-ray diffraction and IR adsorption.

Page 30 of 67
When dissolved, the crystalline structure is lost -> different polymorphs of the same substance will
show the same absorption spectra in solution.
In drug formulation the polymorphs should be stable.
Isomorphous crystals: chemical substances with similar chemical constitution form crystal of
similar shape.
If a solution, about to crystalize, is seeded with a crystal of another, isomorphous substance, an
isomorphous overgrowth is obtained; the solute crystalizes around the immersed crystal.
Another property: formation of mixed crystals.
Size of crystals: depend on conditions
small crystals -> rapid cooling, frequent stirring, almost saturated solution, at boiling point
o
medium crystals: crystalizing from H2O, saturated solution, 60-80 C, slow cooling, no mechanical
disturbances
large crystals: large volume of solution, evaporate spontaneously.
Mechanism of crystallization:
saturated solution; lowering of saturated solution or evaporation of solvent -> excess of solid
material separates -> supersaturated solution.
2 steps:
1: creation of crystalline nuclei;
2: growth of nuclei into crystals.
Process is called seeding.
Usually the pharmaceutical materials are in crystalline forms to achieve chemical and physical
stability. The Amorphous material can be characterized with a random distribution. The molecular
pattern can be described as a frozen liquid with the rheological properties of a solid.
The amorphous solubility is > than the crystal stat due to higher ΔG level.
b)Controlled area and clean area in the manufacture:

CONTROLLED AREA  An area constructed and operated in such
a manner that some attempt is made to control the introduction of
potential contamination (an air supply approximating to grade D
may be appropriate), and the consequences of accidental release of
living organisms. The level of control exercised should reflect the
nature of the organism employed in the process. At a minimum,
the area should be maintained at a pressure negative to the
immediate external environment and allow for the efficient
removal of small quantities of airborne contaminants.  
CLEAN AREA  An area with defined environmental control of
particulate and microbial contamination, constructed and used in
such a way as to reduce the introduction, generation and retention
of contaminants within the area. Note: The different degrees of
environmental control are defined in the Supplementary
Guidelines for the Manufacture of sterile medicinal products.  

Page 31 of 67
14.
a) Emulsions. HLB
The character of emulsions: oil-in-water (O/W) or water in oil
(W/O), depends on whether the material to be emulsified is better
soluble in water, or in oil. The component to be emulsified is
dissolved in the phase in which it is better soluble, and the other
phase is added under uniform rubbing or vigorous shaking.
In order to increase the stability of the emulsion, an emulsifying
agent (polysorbate, sodium lauryl sulfate etc.) is added, which will
ensure a higher degree of dispersion.
Emulsions may also be stabilized by means of colloidal auxiliary
materials that are insoluble in both phases, an example is
hydrophilic silica dioxide.
If the emulsion should contain a solid component that is insoluble
in both water and oil, it must be finely pulverized (to pass through
sieve VII.), rubbed with a small portion of the emulsion, and
added to the preparation subsequently
A more systematic method of selecting emulsifying agents has
been introduced by Griffin with the so called HLB system. The
emulsifiers are characterized by stating the hydrophile-lipophile
ballance as HLB values. These can be calculated according to
different formulas but also be determined experimentally. They
generally lie between 1 and 20. A low HLB value indicates that the
i喩 lipophilic portion of the emulsifier will dominate, a high value
that the hydrophilic portion is predominant. The HLB for a
毖喩 mixture of emulsifiers is calculated in proportion to the
concentrations.
The following changes in the emulsions system may occur during
storage: 
1.) coagulation or flocculation ( the droplets will form loosely
cohering groups) 嶇
2.) Coalescence (the droplets flow into each other)
3.) Phase inversión (an O/W emulsiuon changes into a W/O
emulsion and viceversa)

Page 32 of 67
4.) Creaming (the disperse phase concéntrates at the top) 飇
b) Characterization of particle size: Reactionkinetics in technology
Physical and chemical properties (QUALITY) of products with
dispersed phases may depend on the properties of the dispersed
phases (e.g., particles and droplets). In addition, many processes
deal with dispersed particles. Control of these product properties
and these processes requires a way to describe sizes and shapes of
the dispersed phases.
Physical characteristics:
Physical particle characteristics describe the behaviour of
particles:
 - settling velocity, 
- speed of diffusion,
ㅁ- passage through a screen opening
- electric charge,
- light scattering..
The physical particle characteristics are depending on the size and
form of particles as well as parameters like density, index of
refraction, viscosity.
15.
a) Suspensions:
Suspension
The preparation is essentially similar to that for a mono disperse

suspension with
exception that somewhere during the process a definite quantity of
electrolyte is added to produce the desired degree of flocculation.
the amount of electrolyte needed must be determined by
experimentation.
Procedure might be described as :
– wet the solid

Page 33 of 67
– add electrolyte to flocculate
– add suspending agent
– dilute to volume
The most efficient method of producing fine particles is by dry

milling prior to
suspension. The choice of an app. Suspending agent depends upon
the use of the
products: external or internal, facilities for prep, and duration of
product storage.
Preparations made by extemporaneously for internal use may internal use
include as acaciamethylcellulose
suspending agents acacia methyl cellulose and other cellulose cellulosederivatives
derivates . Sodium alginate and tragacanth agents suitable for
externaluse
external use
sodiumagm ate
include bentonite. Those agents may require high speed
equipment and which are tragacanth.betonite
suitable for internal and external use include aluminium internaleternal
magnesium silicates and aluminiummagnesium
carbomer. silicatesl carbomer
Excipients for suspensions

hydrophilic, colloids:
increase the viscosity of water by binding water molecules,
limiting their mobility or fluidity.
Viscosity is proportional to the cc° of the colloid
ACACIA:
is usually used as the official mucilage which is a 35% dispersion
in
water. The drug contains polymers of salts of arabic acid. The
herapenta
preparation is preserved with 0.15% sodium benzoate. Its used in
productfor extemporaneous production of
individual mixtures and emulsions
patient
TRAGACANTH:
the official mucilage is 6% . the viscosity depends on greatly
on quality and form of standing material and is somewhat on
predictable. More
difficult to use than acacia.
Preservation : methyl hydroxybenzoate.

Page 34 of 67
SODIUM ALIGNATE:
– alginate mucilage is produced at c.c of 1-2%
– alginate acid ppt if the ph falls below
– alginic acid is in bubble in water. Sodium aligenate is used
– aligniates are employed in preparation of suspensions and
emulsions as table
disintegrants.
CELLULOSE DERIVATES:
methyl cellulose. Ethylhydroxytheylcellulose, Ha
carboxyehtylcellulose.
Cellulose derivates are now used in production of pharmaceutical
as viscosity
increasing agents.
They also posses a direct therapeutic use as bulk laxatives.
(for points and dyes. Cosmetics. Foodstuff.etc)
POLYACRYKIC ACID:
polymers or acrylic acid CH2=CH-COOH
when suspended in water they give solutions with a rather low
viscosity. Not
until neutralization with alkali are solutions of high viscosity
obtained, they are
used in low c.c for
suspensions and emulsions not more than 0.1-0.5%
CLAYS:
bentonite and veegum . Chemically they are both silicates and are
anionic in
aqueous dispersion. The forming of gel-like structure on standing
and becoming
fluid on agitation. As suspending agents, they are strongly
hydrated and exhibit
thioxotropy. Betonite is employed in prep. of suspensions for
external app.
Betonite gels are also employed as ointment base.
AEROSIL:
consists of spherical.colloid particles of pure silicate dioxide. Its
prepared by
flame hydrolysis of silicate chloride. Aerosil gives gel formation
with both water

Page 35 of 67
and organic solvents. Its used as glidant in powder mixtures and
tablet.
b) Anomalies in fluidization process:

- Bubbling fluidization: exist when the diameter of the solid is
lower from the other side of surface: power blast
- Channeling bed: geyser technique (air is not observed in the
column when particles are away from each other for different
particle size)
- Separated and slugging bed
- The main disadvantage of G-S fluidization is the uneven
contacting of gas and solid.
- The preparation of the air
- Erosion of the vessel internals
- Attrition of solids; because of attrition, the size of the solid
particles is getting reduced and possibilities for entrapment of
solid particles with the fluid are more
- Detonation danger- take a necessary precaution
16.
a) Rectal dosage forms. Vaginal preparations. Sticks
apposite Rectal preparations:
capsulesolutionintended for rectal use in order to obtain a systemic or local effect, or diagnostic purposes.
Can be: suppositories, rectal capsules, rectal solutions and suspensions, powders and tablets for
suspension
rectal solutions and suspensions, semi-solid rectal preparations, rectal forms, rectal tampons.
sowaers Vaginal preparations:
liquid, semi-solid or solid preparations
Intended for administration to the vagina, usually local effect
moulded Can be: moulded pessaries, vaginal tablets, capsules, foams or tampons.
suppository Moulded pessaries:
tablets solid, single-dose preparations. Various shape, usually ovoid, with volume and consistency suitable
capsules for insertion into the vagina. Also conform to the definition of moulded suppositories in the
pharmacopoeia for rectal preparations.
tampons
Active ingredient: dispersed or dissolved in simple or compound basis - may be soluble or
insoluble, but melting at body temperature or dispersible in water
Tablets: compressed pessaries, solid, single-dose preparations
Capsules: shell pessaries; solid, single dose. Similar to soft capsules, but differ in shape and size;
smooth, uniform external appearance.
Suppository bases:
Fatty bases:
cocoa butter (theobroma oil, butyrum cocoa) - mix of triglycerides; exhibit polymorphism - may
crystallize in any of 4 crystal forms, depending on fusion temperature and rate of cooling. Stable
o o
crystals exist up to melting point of 34-35 C; solidification point at 28 C. Due to transformation
between the different crystal form, it needs to be cold for several days to reach the stable crystal
form.
Witepsol bases:
W35 (adeps solidus 50), H-15, H-12 - 12 different, nearly white, almost oforless.
No polymorphism when melted and cooled. Composed of natural saturated fats, chains: C12-18,

Page 36 of 67
lauric acid most abundant.
Small softening->melting interval, solidification only a few degrees below melting point.
Rapid solidification, contract-> no lubrication.
Contains emulsifier -> absorb limited amounts of H2O
Water soluble/water miscible:

got Polyethylene glycol (PEG) bases/carbowaxes - does not melt at body temp, dissolves in secretins of
macro
rectal mucosa.
PEG 400 is liquid at room temperature
PEG 1000 is soft semisolid
PEG 1500 and 1540 are fairly firm semisolid
PEG 4000 and 6000 are firm wax-like solids (numbers give molecular weights!).
Dissolves slowly, even in excess H2O;
little fluid in rectum and vagina -> slow dissolution, but soften and spread.
Must meet several criteria:

Remain enough for insertion at room temperature, even at warm climates; should not soften below
o
30 C
o
Narrow or sharp melting range (not more than 3 between softening and complete melting)
Inert, compatible with wide range of drugs
Nonirritating and non-sensitizing, stable
b) Parenteral additives and parenteral nutrition:

Validation GMP documentation eachstep
Parenteral additives: every processvalidated to
insure safety
- Water for injection is the most used. Is when water is used as vehicle and to dissolve or dilute a
substance, sterilized water.
- Non-aqueous solvents: water miscle solvents. Glucose (polyethylene), glycerol- ionizing efficacy
agent, polyetilene, glycolà for drugs with low solubility, dimethyl Uk
et in
acetamindeNlactamideàlow toxicity parenteral
- Oily solvent: only for intramuscular administration Solution
- Vegetable oil such as sunflower, soya bean, olive oil
contained
Parenteral nutrition(PN) refers to the provision of nutrients by the pyrogens
intravenous route. In general, PN should only be used when it is tr
not possible to supply nutrition using the GI tract ie when dearer
intestinal failure is present. Total Parenteral Nutrition (TPN)
Prospective vaidatio
implies that all macronutrient (carbohydrate, nuitrogen and lipid) Retrospective
and micronutrient (vitamins, trace elements and minerals) and documentary
fluid requirements are met by an intravenous nutrient solution and hat theprocessis evide t
no significant nutrition is obtained from other sources. Some doingwhatisbelieve
patients treated with PN can absorb some fluid and nutrition taken todo
orally and in these patients PN is a supplement to their oral concurrent
intake. monitorcritical
processingstepsI
17. endproducttesting
a) Ointments, cremes, gels and pastes. Dermal preparations: Revandation
changestoproduct
Ointments are semisolid preparations for treatment of the skin or plantlprocess
mucous periodicchecking
membrane. Their consistency is determined by the properties and increaseIdecrease
inbatchsize

Page 37 of 67
the ratio of the
components.
The way of producing ointments containing a medicament is
determined by the characteristics of the active ingredients and
those of the basematerial.
- Types of ointments according to the preparation:
1. Ointment of solution type. ungnenmmsimpiex.oleosum.emui.ficansnomination
2. Ointment of emulsion type. who hydro philnonion Ianion
sum emollients ol wi hydro
3. Ointment of suspensions type. Ema Stari ni
ayaan vaseimam
4. Composite ointments. acid boric
Paste or cream is a semisolid preparation containing one or more

drug
substances for topical application. Highly viscous ointment
containing a large
amount of powder.
Gel: consists of liquids gelled by means of suitable gelling agents:

Hydrophilic gels: hydrogels are preparations whose bases usually
consist of
water, glycerol or propylene glycol gelled with suitable gelling
agents such as
tragacanth, starch, cellulose derivates, carboxyvinyl polymers and
magnesiumaluminum
silicates.
Hydrophobic gels: oleogels are preparations whose bases usually
consist of
liquid paraffin with polyethylene or fatty oils gelled with colloidal
silica or
aluminium or zinc soaps.
b) Autoclaving procedure and testing: 1210C 20m in

Autoclaves are used to sterilize biological waste products prior to
disposal in regular trash. These devices must be tested to ensure
that sterilization performance meets the California Medical Waste
Act and United Stated of Agriculture-Animal and Plant Health
Inspection Services requirements, and Centers for Disease Control
and Prevention guidelines. There are three indicators that may be
used to detect the efficacy of the autoclave process: Physical:
pressure and temperature recording devices, Chemical: indicators
temperature
that changeerrs co
color after being exposed to specific temperatures, sensitivetape
ㅡㅡ
such as temperature sensitive tape. The color change upon whitesblack

Page 38 of 67
exposure to the given temperature, and Biological:
Bacillusstearothermophilussporesare used, due to its resistance to
ignis_
一
heat, for the testing that measures the biological performance of
the autoclave process.
Autoclave Testing Process:

- It is recommended that at least two spore ampules (Bacillus
Stearothermophillus) are used per cycle.
- Label the spore ampules with the proper information. Such as
date, autoclave number, etc.
- Place the spore ampoules in a horizontal position inside a
Biohazardous bag with representative materials to be
sterilized. (Biohazardous bag should be closed with autoclave
tape)
- Select appropriate cycle to process the load.
- Once the cycle is completed, allow autoclave to decompress
and cooldown
- Remove the load from autoclave and allow it to further cool
down
- Retrieve the spore test ampoules from the load.
Note: the chemical indicator tape changes from white to black
when exposed to steam.
18.
a) Ocular, ear and nasal preparations:
Eye preparations are sterile liquid, semisolid or solid preparations
intended for administration upon the eyeball and/ or to the
conjuctiva or for insertion in the conjunctival sac.
Several categories of eye preparations may be distinguished:
- Eye drops
- Eye lotions
- Powders for eye drops and eye lotions
- Semisolid eye preparations
- Ophthalmic inserts
Requirements for an ophthalmic solution:
- Sterlity (Ophthalmic solutions are prepared in a previously
disinfected part of the pharmacy segregated for this use only:
in a „manipulator hood” or sterilize box. A special set of
一

Page 39 of 67
Sterilizedutensils W lamp sterilizebox washhands
sterilized or disinfected atensils and dispensing containers are
to be used. Strict attention must be paid to exclude any
possibility of contamination during the work, to fulfil the
conditions of sterility as described above )
- Selection of preservatives ( requirements for preservatives:
rapid bactericidal action against MO, specially P. aeruginosa,
non-irritant, the absence of incompatibilities, good stability)
- Tonicity (An ophthalmic solution is considered isotonic when
its tonicity is equal to that of a 0.9% sodium chloride solution
(290 mOsm/l). However the actual osmotic pressure of
aqueous intra-ocular fluid is a little bit higher than tears and
measures at 305 mOsm/l. )
- pH
- stability
- viscosity ( the viscosity of eye drops is increased, the time of
contact with the eye will be 一一longer and the drug effect will be
improved.
一
Viscosity-increasing additions are therefore used
in the formulation of several preparations. Cellulose
derivatives ( methylcellulose, hydroxypropyl
methylcellulose) or polyvinyl alcohol are generally used. )
Nasal drops:
Nasal preparations are liquid, semi-solid or solid preparations
intended for administration to the nasal cavities to obtain a
systemic or local effect. They contain one or more active
substances.
Nasal preparations are as far as possible non-irritating and do not
adversely affect the functions of the nasal mucosa and its cilia.
Aqueous nasal preparations are usually isotonic and may contain
excipients, for example, to adjust the viscosity of the preparation,
to adjust or stabilise the pH, to increase the solubility of the active
substance, or to stabilise the preparation.
Nasal preparations are supplied in multidose or single-dose
containers, provided, if necessary, with a suitable administration

Page 40 of 67
device which may be designed to avoid the introduction of
contaminants
Unless otherwise justified and authorised, aqueous nasal
preparations supplied in multidose containers contain a suitable
antimicrobial preservative in appropriate concentration, except
where the preparation itself has adequate antimicrobial properties.
Nasal drops and liquid nasal sprays are solutions, emulsions or
suspensions intended for instillation or spraying into the nasal
cavity. Nasal sticks. Nasal drops are usually supplied in multidose
containers provided with a suitable applicator.
Otic preparations:
Otic preparations are liquid, semi-solid or solid preparations
intended for administration to the otic cavities. They contain one
or more active substances.
Ear preparations contain in general antiseptic, antimycotic,
analgesic and deodorant active ingredients. Usual solvent: are
dilute alcohol, dilute hydrogen peroxide and boric acid solution.
re TE's
Otic preparations are as far as possible non-irritating and do not
have adversely affect in the otic cavities. Otic preparations may
contain auxiliary materials or excipients, for example, to adjust ironic 은
the viscosity of the preparation, to adjust or stabilise the pH, to
increase the solubility of the active substance, or to stabilise the
preparation.
Otic preparations are supplied in multidose or single-dose
containers, provided, if necessary, with a suitable administration
device which may be designed to avoid the introduction of
contaminants.
Solvents: Dsitilled water, propylene glycol, polyethylene glycol,
oily solvents
b)Rheological testing and behaviour:

Rheology is the branch of science dealing with the deformation
and flow of
matter.
In pharmacy, there is many liquid and semi-solid formulations

Page 41 of 67
where the
knowledge of liquid behavior is essential for optimum formulation
design.
NEWTONIAN FLOW:
the flow properties of liquids such as water, alcohol and
glycerol are expressed on the basis of viscosity determination : F=
viscosity(A)dv/dx F/A is the shearing stress ,
dv/dx is rate of the shear.
Viscosity: f/A / dv/dx = shearing stress/ rate of share.
NON NEWTONIAN LIQUIDS:

newtons equation doesn’t apply to non homogenous
solutions and systems such as colloidal solutions, suspensions,
emulsions and ointments.
Plastic flow:
is found chiefly in suspensions of different kinds and in
ointments.the particles adhere each other to form structural forms.
Pseudplastic flow:
the main types of solutions are those containing long-chain
molecules and micelles. Cellulose. Initially the curve will follow
the same course as in newtonian liquid curve but will later show
on increasing upper bend.
The viscosity will this decrease with increasing shearing stress.
Dilatent flow:
higher viscosity is obtained with increasing shearing stress.
Thus stirring or agitation will cause a thickening of the material
dialtency is
found in c.c suspensions.
Thixotropy:
the changes in the structure of the system caused by variations of
the shearing stress occur instantaneously.
A thixotropic consistency maybe beneficial property in medicine.
This suspension of this type will flow easily when shaken so that
is can be poured from container.
Later when it has been left to stand for a while, it will re-assume
p+s thick consistency which effectively present in segmentation

Page 42 of 67
19.
a)Inhaled preparations, medicated aerosols, foams:
Preparations for inhalation are liquid or solid preparations
intended for administration as vapours or aerosols to the lung in
order to obtain a local or systemic effect. They contain one or
more active substances that may be dissolved or dispersed in a
suitable vehicle. Preparations for inhalation may, depending on the
type of preparation, contain propellants, cosolvents, diluents,
antimicrobial preservatives, solubilising and stabilising agents,
etc. These excipients do not adversely affect the functions of the
mucosa of the respiratory tract or its cilia. Suspensions and
emulsions are readily dispersible on shaking and they remain
sufficiently stable to enable the correct dose to be delivered. 
Preparations intended to be administered as aerosols (dispersions
of solid or liquid particles in a gas) are administered by one of the
following devices: – a nebuliser; – an inhaler (pressurised metered-
dose inhaler, non-pressurised metered-dose inhaler or powder
inhaler). Several categories of preparations for inhalation may be
distinguished: – preparations to be converted into vapour; – liquid
preparations for nebulisation; – pressurised metered-dose
preparations for inhalation; – non-pressurised metered-dose
preparations for inhalation; – inhalation powders.
Aerosols are defined as colloidal systems of very finely
subdivided liquid or solid particles dispersed in and surrounded by
a gas. Classifications of Aerosol Products:
• Space sprays: Disperse the active ingredients as a finely divided
spray with the particle no longer than 50 micron in diameter.  
• Surface coating: Disperse larger particles, generally produce a

wet or coarse spray.  
• Aerated sprays: Disperse medicated foams, vaginal foams,

shaving cream.  
Advantages of the Aerosol Dosage form:

1. Minimum Contamination  
2. Maximum Stability  

Page 43 of 67
3. Reduces the irritation; cooling effect  
4. Easy to control: physical form; particle size; dose  
5. Clean process; require no wash-up  
The aerosols are used in pharmacy for local or systemic delivery

of drugs. Over the last 10 years the importance of inhalation
therapy for asthma has increased, with virtually all asthmatics now
using aerosolized medication (in one form or another) for the
treatment of their asthma.
Foams: Commonly foam is defined as a dispersion of gas in a
liquid or a solid, whereas the volume fraction of gas in the foam is
mostly between 0.5 and 0.9. The bubble size is mostly between
0.1 and 3mm. Foams can be classified into 2 types: liquid and
solid foams. Solid foams can be generated when the liquid phase
is changed into gel or solid phase after foam formation. These
systems are alsoknownunder the definition of dry foam, xerogel or
sponge and often used as sore cover materials. They may contain
disinfecting agents, antibiotics or steroids. Mostly, collagen or
gelatine sponges which can absorb a lot of ichor because of their
high capillarity are used. These materials also are available for a
temporary skin replacement after burn or in cosmetic surgery Pure
liquids do not foam. The presence of a foaming agent is essential
for foam generation and stabilisation.
b)Study of drying process:

Drying process consist in the removal of a liquid from a solid by evaporation.
During drying, the following two processes occur :
Heat transfer to solids from the surrounding air
Mass transfer as liquid or vapour within solids and as vapour from solids surface
一一
Energy applicable for drying

• Mechanical
• Heat
• Microwave
• Sonic
Heat transfer has different methods

a) Convection : heat supply by gas
1
b) Contact : heat supply by direct contact
c) Radiation
d) Inner heat : chemical transformation

Page 44 of 67
Drying rate influencing factors
• Bulk density and particle density influence the resistance of airflow and the diffusion of the
internal water
• Size of the individual particles influence the internal heat diffusion for large particles.
• Temperature of the incoming product
• Vapour pressure : when air reach the maximim amount of vapour
• Relative humidity : the ratio of actual vapour pressure to the

saturation
• Air movement : the movement of the layer of air in immediate contact with the solid is more
slowly and has a higher pressure than the main stream (boundary layer effect)
• Supply of heat
• Movement of moisture in the solid material
• Airflow rate : determine the overall process efficiency
Spray drying
Is a unique method to convert a solution, suspension or emusion into a solid powder in one step. It
is a widely estabilished process in many industries such as pharmaceuticals, food, chemical or
material science.
Atomization of a solution of one or more solids via a nozzle, spinning disk, or other device,
followed by evaporation of the solvent from the droplets is termed spry drying.
Advantages
• Applicable on drying of sensitive materials such as vitamines, hormones, antibiotics, vegetable
extracts.
• Useful solution for increase stability
• The process is quick, continuous
• Optimization of drug delivery, due to the large inner surface-active
Disadvantage
energy demanding process, explosion dangerous (solvent and powder)
The nature of the powder it results from several parameters like

• initial solute concentration
• size distribution of droplets produced
• Rate of solvent removal

Page 45 of 67
20.
a) Powders, granules and their tests. Homogenization, granulation procedures:
Powders for internal use: Advantages and Disadvantages, Can

generally administer fairly large quantities (e.g. pour directly onto
back of tongue, stir in beverage, mix with apple sauce etc.). May
be preferred by some patients who have trouble swallowing
“objects,” such as tablets or capsules. Taste may be a problem 
Powders for internal use may be dispensed in bulk or in divided,
individually packaged portions [doses], depending mainly on the
potency of the powder. –Bulk powders for internal (oral) use are
usually granulated.
Powders for external use: Powders dispensed in bulk intended for
topical application are called dusting powders, Common diluents
are starch and talc, More easily applied when dispensed in sifter-
top shaker containers Most sifter-top containers are not “tight
containers”. May not be suitable if contains volatile components
or if must be protected from atomospheric moisture
Granules: Flow better than powders (granulation is a
sizeenlargementprocess) and have better compactibility than
powders (binders) –advantage in making tablets or filling capsules
(feeding of high-speed equipment) Less surface area per unit
weight than powders –More stable to atmospheric
moisture/oxygen –Less likely to cake in the container than
powders.
Tests:
Mechanical comminution is a mainly uncontrolled process. A
general problema if milled products is their powder properties,
which habe to be considered. Mechanically micronized substances
are electrostatically charged and, in most cases, they are
agglomerated due to their cohesive behavior. Further, a
mechanical comminution process generally results in a broad
particle size distribution and heterogeneous particle shapes. Due to
the high energy input, a milling process is ineffective. The high

Page 46 of 67
energy input affects the surface properties, and consequently the
bulk properties, of the resulting product. The high energy input
can cause a disruption of the crystal lattice on the particle surface
and the creation of defects, such as the formation of amorphous
regions
Particle size reduction: common reasons for reducing particle size:
- Create appropriate particle sizes for subsequent processing or
end use (e.g. inhaled particles).
- Create a free-flowing material.
- Improve material blending and prevent segregation by making
different sized products with similar particle size
distributions.
- Increase the material’s surface area to improve a material’s
reactiveness, dissolution (and bioavailability), or drying
efficiency.
- Control a material’s bulk density by creating a particle size
distribution consisting of a matrix of larger particles with 
smaller particles filling the voids between the larger particles.
b) Testing pyrogens, bacterial endotoxins:
Infusions with sugar contain are a good culture media for dangerous bacteria like Pyrogens.
Pyrogen is any substance that can cause fever. The are endotoxins (lipopolysaccharide (LPS) found
as part of the cell wall of GRAM- and are released upon bacteria cell lysis.
The removal of pyrogens is done by tratment of the solution with 0.5% of Active coal.
Than the solution is filtered through a glass filter for remove the carbon.
If we use the autoclave in a neutral solution we can find 5-hydroxy-methyl-furfural as a
decomposition compound of glucose.
We can detect it with the spectrometry (284 nm)
autoclave x becauseof decompositioncompound
of glucose 5hydroxy methyl furfuran
Pyrogen detection
Rabbit test : inject to the rabbit the sample and observe the response in the body temperature.
LAL test : Limulus amebocyte Lysate a reaction is observed in this lysate (colour change)
21.
a) Pharmaceutical pellets. Pills. Multiparticulate systems.
Med. Chewing gums:
Pellets offer a high degree of flexibility in the design and

Page 47 of 67
development of oral dosage forms.
They can be divided into desired dose without changes in the
formulation or process.
Pellets, taken orally, disperse freely in the GI tract, maximize drug
absorption, minimize local irritation of the mucosa by certain
irritant drugs.
Pellets can be defined as small, free flowing, spherical particulates

manufactured by the agglomeration of fine powders or granules of
drug substances and excipients using appropiate processing
equipment
The main steps of the processess
1. Dry mixing of ingredients to achieve a homogenous powder

dispersion
2. wet massing to produce a sufficiently plastic wet mass
3. Extrusion to form rod-shaped particles of uniform diameter
4. Spheronization to round off these rods into spherical particles
5. Drying to achieve the desired final moisture content
6. Screenin (optional) to achieve the desired narrow size
distribution
Pills: A typical formula or prescription for pills would give the

weight of each ingredient required to make one pill and state the
number of pills required. Multiplying these two figures together
gave the quantities to be weighed. The ingredients were then
thoroughly mixed using a pill mortar and pestle.
It was now necessary to add an excipient, an inert substance to
bind all the ingredients together to form a stiff, workable mass.
The substance of choice, for most purposes, was syrup of liquid
glucose - a very thick and viscous syrup. This had to be added a
drop at a time whilst the ingredients were vigorously worked in
the mortar. Just enough was added to form a noncrumbling,
stiff, pliable mass.
The mass now had to be divided accurately into equal parts
equivalent to the number of pills ordered. In earlier days this
procedure was carried out on a pill tile. The mass would be rolled
into a ball, then gradually rolled into a long, even pipe. By
measuring the pipe and dividing by the number of pills, the length
of each dose could be calculated and the pipe cut into portions.

Page 48 of 67
Later tiles had graduations so that the pipe could be rolled to a
specific length equal to the required number of graduations.
Foams: Commonly foam is defined as a dispersion of gas in a

liquid or a solid, whereas the volume fraction of gas in the foam is
mostly between 0.5 and 0.9. The bubble size is mostly between
0.1 and 3mm. Foams can be classified into 2 types: liquid and
solid foams. Solid foams can be generated when the liquid phase
is changed into gel or solid phase after foam formation. These
systems are alsoknownunder the definition of dry foam, xerogel or
sponge and often used as sore cover materials. They may contain
disinfecting agents, antibiotics or steroids. Mostly, collagen or
gelatine sponges which can absorb a lot of ichor because of their
high capillarity are used. These materials also are available for a
temporary skin replacement after burn or in cosmetic surgery Pure
liquids do not foam. The presence of a foaming agent is essential
for foam generation and stabilisation.
二
Sticks: Sticks are solid preparations intended for local application.
They are rod-shaped or conical preparations consisting of one or
more active substances alone or which are dissolved or dispersed
in a suitable basis which may dissolve or melt at body
temperature. Urethral sticks and sticks for insertion into wounds
are sterile.
Tests: Urethral sticks and sticks for insertion into wounds comply
with the test for sterility.
Labelling: the quantity of active substance(s) per stick, for urethral
sticks and sticks to be inserted into wounds that they are sterile.
Medicated chewing gums: are solid, single-dose preparations
with a base consisting mainly of gum that are intended to be
chewed but not swallowed. They contain one or more active
substances which are released by chewing. After dissolution or
dispersion of the active substances in saliva, chewing gums are
intended to be used for : — local treatment of mouth diseases, —
systemic delivery after absorption through the buccal mucosa or
from the gastrointestinal tract. PRODUCTION Medicated chewing
gums are made with a tasteless masticatory gum base that consists
of natural or synthetic elastomers. They may contain other
excipients such as fillers, softeners, sweetening agents, flavouring

Page 49 of 67
substances, stabilisers and plasticisers and authorised colouring
matter. 
b) Replacement factor of suppositories preparations:
Determined by:
10 “empty” suppositories, made from base material, average weight determined.
Suppositories of different concentrations of drug prepared, and average mass is determined
f = mass of the base replaced/mass of replacing medication)

Thus: 1g of the medication will replace ((100×(E0 - G))/(G×X))+1g of the base material
E0 - mass of “empty” suppository,
G - mass of suppository with drug
x Ii of AI
If drug has density lower than base, f > 1.0, if higher then f < 0.
Relative density:
density of medicament relative to drug base: q = 1/f
Determine the amount of base to be added in the case of formulation any volume of medicament of
known f value:
Gm = E0 - (g×f)
Gm - mass of base required to make one suppository,

g - total mass of the medicament in a suppository.
22.
a) Pharmaceutical capsules. Micro and molecular
encapsulation:
Encapsulation refers to a range of techniques used to enclose medicines in a relatively stable shell
known as a capsule, allowing to them to be taken orally or as suppositories.
The two main types are
Hard shelled capsule: made using gelatin and contain dry, powdered ingredients or miniature
pellets, made by extrusion or spheronization.
Soft shelled capsule: primarily used for oils and for active ingredients that are dissolved or
suspended in oil.
The advantages are: improved bioavailability and drug stability, protection against oxidation,
photodegradation and hydrolysis in lipophilic systems).
Can be used as substitutes for suppositories.
Disadvantages are: high manufacturing cost.
Both of this capsules are made from aqueous solutions of gelling agents like
• animal protein (mainly gelatin)
• Plant polysaccharides or derivatives
Other ingredients can be added to the gelling agent solution like plasticizers such as glycerin and/or
sorbitol or decrease the capsule's hardness, colouring agents, preservatives, disintegrants, lubricants
and surface treatment.
Gelatin capsules are composed of gelatin manufactured from the collagen of animal skin or bone, or
from cellulose.
spraydrying.coaeration 이 w emulsiondroplets are coated in poly electrolytes

likegelatinl Arabic gum shellformation concentric nozzles that have
Shell corecoating
Page 50 of 67
Tests
• Uniformity of content - Capsules with API content less than 2mg should be tested for the
uniformity of content of single-dose preparation. The preparation fails to comply with the
test if more than 3 individual contents are outside the limits of 85 to 115% of the average
content or if one or more individual contents are outside the limits of 75% to 125% of the
average content.
• Uniformity of mass.
Dissolution
b) Tabletting parameters:
Solid dosage forms of medicinal substances usually prepared with
the aid of suitable pharmaceutical adjuncts. Mostly intended for
oral administration
Advantages: 
- Unit dose 
- Simpletoidentify 
- Lend themselves to special release forms
- Most stable of all oral preparations.
Disadvantages: 
- Some drugs resist compression.
- Problems with bioavailability
Basic requirements: Drug content of individual tablets have to be drugcontentsimilar
varied within narrow limits. Having smooth surface, adequate smoothsurface
breaking strength and these properties stay changeless during adequatestrength
packing and delivery. Support drug release, for achieving optimal
therapeutic effect. Original properties stay unchanged during
storage.
Basic requirement is the chemical purity of the active agent. 

Among the physical properties the melting point, adhesive
properties
and crystal shape have the main interest. Low melting point (below
70-75°C) can cause difficulties during

Page 51 of 67
compression, even in case of more active agents eutectics can be
developed.
adhesive properties can be responsible for sticking to the
compressing tools, especially to the dyes. From physiological
point of view, the biological degradation of the active agent, and
the healthcare of the personnels have themain interest
mass uniform
disintegratewithin is min on 37
friabilityloss I Ii 740N
23.
a) Tablets and Tablet preparation:
Tablets are solid dosage forms of medicinal substances, usually prepared with the aid of suitable
pharmaceutical adjuncts. Mostly intended for oral administration.
Advantages
• Unit dose
• Special release forms
• most stable of all oral preparations
Disadvantages
• Some drugs resist compression

• Problems with bioavailability
Type of tablets
• Disintegrating tablets
• Effervescent tablets
• Soluble tablets
• Lozenges
• Controlled release tablets
Types of administration routes
• Oral
• Per os
• Parenteral

Page 52 of 67
• External
• Soluble
Typical composition of uncoated tablet
API
Filler: to give a size of the tablet, should the inert, water soluble, good mechanical properties, non
hygroscopic. Can be
• Sugars ( lactose, mannitol…)
• Salts (Calcium carbonate…)
• Polymers (cellulose…)
Binder: is added to increase the cohesion between the particle (gelatin, starch, PVP...)
Lubricant and glidants: used to increase flowability of powders (magnesium stearate, polyehylen
glycol).
Disintegrants: ensure that the tablet breaks into small pieces when in contact with water. Surfactants
can be used, they will adsorb to interfaces and in water increase the hydrophilicity of that interface.
Coloring and flavoring agents
rotarypress upperpunchpushdown
lowerpunchpushup
Tabletting processTesting of tablets
• Mass uniformity
• Disintegration
• Friability
• Strenght
• Content uniformity
b) Study of stability of emulsion:

The following changes in the emulsion system may occur during
storage:
- Coagulation or flocculation (the droplets will form loosely
cohering groups)
- Phase inversion ( an O/W emulsion changes into a W/O
emulsion and vice versa)
Determining the type of emulsion:

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- Dye-solubility method: the emulsion is easily coloured by a dye
which is soluble in the external phase of the emulsion.the test is
often made with methylene blue (water-soluble) or sudan III (oil-
water).
- Drop-dilution method: the emulsion can be raidly diluted with
its external phase. Therefore, if a drop if the emulsion is
rapidly dispersed in water, the emulsion is of the O/W type.
- Conductivity method: An O/W emulsion conducts a current,
whereas W/O emulsion does not.
The character of emulsions: oil-in-water (O/W) or water in oil

(W/O), depends on whether the material to be emulsified is better
soluble in water, or in oil. The component to be emulsified is
dissolved in the phase in which it is better soluble, and the other
phase is added under uniform rubbing or vigorous shaking.
In order to increase the stability of the emulsion, an emulsifying
agent (polysorbate, sodium lauryl sulfate etc.) is added, which will
ensure a higher degree of dispersion.
Emulsions may also be stabilized by means of colloidal auxiliary
materials that are insoluble in both phases, an example is
hydrophilic silica dioxide.
If the emulsion should contain a solid component that is insoluble
一一
in both water and oil, it must be finely pulverized (to pass through
sieve VII.), rubbed with a small portion of the emulsion, and
added to the preparation subsequently.
24.
a) Coated dosage forms:
The coating is required for masking odour and taste, enhance
mechanical strenght, visual attractiveness, API can be
incorporated in the coating,
The major reasons for coating are: pritection of AI,
safety/identification, taste/odourt barrier, improved appearance,
Brand identity, improved handly on high speed automatic filling,
functional coatings.
Sugar coating: sugar coating has been the most extensively

Page 54 of 67
l waterproofing 2 subcoating3 semotheringwounding 4 finishinglcoloring
employed method but is at present being superseded by film 5 polishing
coating techniques. Film coating of tablets in contrast is a
relatively new technology dating back to the 1950s. Most newly
developed coated products are film coated and water is now the
first choice solvent for new film coated formulations (tablets,
microcapsules, pellets).
Advantages:
- Protects drugs from the effect of air and humidity
- Masks unpleasant odor and taste
- Enhances the appearance of compressed tablets
Disadvantages:
- Process is tedious and time-consuming
- Requires the expertise of highly skylled technician
- The Tablet size and weight are almost doubled
- Batch to bacth variability
- Time and expertise requiered for the process
Film coating: Film coating involves depositing a material

consisting of a polymer, plasticizer, colorant and opacifier onto the
surface of a granule or tablet. Coatings may be used to improve
appearance, protect the drug from light, to control its release into
the body.
ADVANTAGES
• Low abrasion, smooth surface  
• Good flow behaviour  
• Masking of taste and smell  
• Good protection against light, air and moisture  
• Impervious separating layers in the case of  multi-layer
composition  
• Systematic release of active ingredients modified
  release

Page 55 of 67
main
• Retardation, delayed dissolving   iii temp
forming
• Low hygroscopicity  
• Visual attractivenes   colorbrandname
b) Electrolite containing infusion:

isotonic infusions: 0.9% NaCl solution, Ringer solution,
sodium lactate-sodium chloride solution,
b) full electrolyte infusions (resembling electrolyte content of
blood plasma): Ringer’s lactate,
c)hypotonic infusions (electrolyte concentration lower than
plasma),
d) hypertonic infusions (containing higher electrolyte
concentration than plasma),
e) solutions for correcting acidosis and alkalosis acidosis: sodium
lactate, sodium bicarbonate, Tris buffer (trometamol), alkalosis:
ammonium chloride, L-lysine hydrochloride,
f) for producing an osmotic diuresis: mannitol, urea.
25.
a) Transdermal and other therapeutic systems:
Transdermal patches are flexible pharmaceutical preparations
cantaining one or more API. They are intended to be applied to
the unbroken skin in order to deliver the API to the systemic
circulation after passing through the skin barrier-
Topical medication with systemic effect; drug absorbed through

skin; rate controlled, transdermal drug delivery.
Advantages
• avoids GI tract

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• no GI distress or other physiological contraindications of the
oral route
• can provide adequate absorption of certain drugs
• increased patient compliance
• no first pass metabolism
• effective use of drugs with short biological half life
• administration of drugs with narrow therapeutic windows
• controlled plasma levels of very potent drugs
• drug input can be promptly interrupted when toxicity occurs
Disadvantages:
• Not for drugs requiring high blood plasma concentration
• adhesive may not adhere well to all types of skin
• may cause skin irritation or sensitization
• uncomfortable to wear
• may not be economical
Types:
• Membrane controlled TTS - Tranderm-Nitro, Catapress-TTS,
Estraderm - Drug reservoir is sandwiched between a drug
impermeable metallic plastic laminate and a rate controlling
membrane. Advantage: Constant drug liberation and blood level;
disadvantage: membrane can be damaged
一二
• Matrix controlled TTS - Nitro-Dur - Reservoir: drug solids
dispersed in a hydrophilic or lipophilic polymer matrix.
Advantage: It has no dose dumping effect; disadvantage:
liberation dose not constant
• Micro-reservoir type TTS - Nitrodisc - combination of a
reservoir and matrix type
• Adhesive type TTS - Frandol, Deponit - Drug incorporated
directly into adhesive polymers (polyisobutylene, polyacrilat).
Disadvantage: drug liberation not constant
• Multilayer adhesive type TTS
• Ultrasound controlled TTS - pore opening, thermal effect,
mechanical effect
• Electronically controlled TTS - High MM, hydrophilic drugs
(peptides, proteins), salts
• Magnetically controlled TTS
• Responsive TTS

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b) Test of suspension:
Viscosity: the resist to flow
Thixotropy: eversible behaviour of certain gels that liquefy when

they are shaken, stirred, or otherwise disturbed and reset after o_
being allowed to stand. The Greek words thixis (stirring or
shaking) and trepo (turning or changing).
Precipitation method: During the precipitation alteration of the
solubility conditions (pH or addition of a second solvent) results
in precipitation of solid particles. Dispersion method. Solid
components should be dispersed in liquids (mortar, ball mill,
colloid mill) The dispersed part wettability can be facilitated after
addition of surfactant such as Polysorbate.
26.
a) Improvement of solubility and absorption (bioavailability):
The Bioavailability is the rate and extent to which the active

ingredient or active moiety is absorbed from a drug product and
becomes available at the site of action.
From the pharmacokinetic view, BA data for a given formulation
provide an estimate of the relative fraction of the orally
administered dose that is absorbed into the systemic circulation
when compared to the BA data for a solution, sustension or
intravenous dosage form.
4 Common sources of inappropiate BA

• The API is not released from the pharmaceutical form in time
to constitute a solution that is easily absorbed.
• The amount of drug release through dissolution undergoes
degradation, could become adsorbent or form an insoluble
complex
• The API fails to coss the GI membraneIntense metabolism or
rapid elimination occurs right after the API is absorbed
The BA of an oral drug depends on its solubility in aqueous media

Page 58 of 67
bioavailabilitydependson drugsolubility in aqueous media over the pH I 7 is
over the ph range of 1.0-7-5 and the rate of mass transfer across
biological membranes.
The poor water solubility of many drugs is the limiting factor.
Possibilities to improve BA:

Improvement of dissolution
Solubility increase
The role of micronization as particle size reduction methods

consider the optimization of physicochemical properties,
dissolution enhancement and ensuring appropriate bioavailability.
This concept can be understood with the Noyes-Whitney equation,
where the particle characteristics influence the active surface
dX : Change of the
concentration of the dissolved
drug
dt : Change of time
A : Surface area at the solid-
liquid interfaces
cs : Solubility
Xd : amount of drug dissolved
V : Volume
D : Diffusion constant
h : Diffusion boundary level
Micronization offers a good strategy for enhancing the dissolution
rate.
The effective surface area dipends also on wetting of the particle
active surface.
Micronization sometimes results in a decreased dissolution rate
due to agglomeration.
To avoid that we should use surface stabilizator like hydrophilic
polymers (PVA, PEG….)
Other methods for increase the solubility
• Salt formation
• Building polar groups in the molecule

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• Complex formation
• Application of hydrotropic materials – Application of
materials containing hydrophilic polar groups (EtOH,
glycerol….)
• Application of solubilizing agents (Surface active agents in
small concentrations)
Solubility and pka

Weak electrolytes exhibit a solubility change as a function of ph.
The key parameter affecting solubility of weak electrolytes is the
pka of the compound
Improvement of dissolution with cyclodextrins
These cyclic glucose polymers have hydrophilic “outer surfaces”
T
and hydrophobic interior cavities where can host drug molecules.
The sulfobutyl form in particular ara
has excellent solubility.
The can be administered also by injection because are not toxic.
Absorption Enhancing agents
Changing membrane fluidity, viscosity, destruct junctionsuld be
pharmacologically inert
non toxic
An absorption enhancer should have a rapid and reversible onset
of action
be chemically and physically compatible with other formulation
b) Preparation of microcapsules:
By coacervation:
• Oxyltetracyline (OTC) calcium (Calcium dioxttetracycline chelate salt) is formed in the
on.women
solution.
• Gelatin is added as a coating polymer, and pH is adjusted to 5.5 -> isoelectric point of gelatine
minimal solubility of OTC complex -> coacervation of precipitated complex happens - the
substance will be separated as an aggregate of colloidal particles, held together by
electrostatic forces.
• The walls can be hardened by e.g. formaldehyde treatment -> sustained release preparation
can be made.
Efficiency of micro-encapsulation: collect capsule by filtration, dissolve in acid, OTC content

determined by spectrophotometry, on basis of color intensity of the complex formed with ferric ions
By fluidization:
a) coating of NaCl or KCl particles with stearin using fluidizer-granulating apparatus

b) Examination of release of active ingredient form coated particles
27.

Page 60 of 67
a) Colloidal drug-carrier systems, significance of
nanotechnology:
Drug delivery is an important issue, especially with a new generation of therapeutics, which are
either unstable in the biological environment, have poor transport properties across biological
membranes, are insoluble in water, or have very low bioavailability.
Nano-sized drug carriers can address some of the above issues and enhance their therapeutic
efficacy.
Nano-sied drug carrier system:

Solid lipid nanoparticles were developed at the beginning of the 1990s as an alternative to emulsion
and liposimes for controlled drug delivery. These particles are made from solid lipids and are
stabilized by surfactants. SLN can be formulated using highly purified TAG, complex glyceride
mixtures, ore ven waxes. SLN have certain advantages over liposomes or emulsion for drug
delivery applications, such as their good tolerability and biodegradation, and their use in a wide-
range of drug delivery applications, such as to improve ocular bioavailability of drugs. For
targetting of drugs to the brain, and for drug delivery via parenteral, pulmonary, and dermal routes.
These can be made “steah” by incorporating polyoxyethylene glicol or pluronics into the
formulation so that they are not recognized by the body’s defense system and cleared rapidly by the
reticuloendothelial system. Stealth SLN have been shown to increase the tumor accumulation of
antitumor antineoplastic agents, as well as can trnasport drugs to the brain which are otherwise incapable or
crossing the BBB.
b) Parametric release: sterilitytest없이출고 savestimemoneyresources

A system of release that gives the assurance that the product is of
the intended quality based on information collected during the
manufacturing process and on the compliance with specific GMP
requirements related to Parametric Release.
At present Parametric release can only be approved for products
terminally sterilized in their final container. Sterilization methods
according to European Pharmacopeia requirements using steam,
dry heat and ionising radiation may be considered for parametric
release
Sterility Assurance System
The sum total of the arrangements made to assure the sterility of
products. For terminally sterilized products these typically include
the following stages: (a) Product design. (b) Knowledge of and, if
possible, control of the microbiological condition of starting
materials and process aids ( e.g. gases and lubricants ).
(c) Control of the contamination of the process of manufacture to
avoid the ingress of microorganisms and their multiplication in the
product. This is usually accomplished by cleaning and sanitization
of product contact surfaces, prevention of aerial contamination by
handling in clean rooms, use of process control time limits and, if

Page 61 of 67
applicable, filtration stages.
(d) Prevention of mix up between sterile and non sterile product
streams. (e) Maintenance of product integrity. (f) The sterilization
process.
essential at theend
28.
a) Parenteral preparations, injections, infusion. Manufacture
of sterile preparations. Clean room, isolators:
Definition: parenteral preparations are sterile dosage forms
intended for administration by injection under or through one or
more layers of the skin or mucous membrane.
pharmaceutical products: single-and multiple-dose small-and
large-volume parenterals.
solvency
large volume parenterals = infusions: solvent is water small infusionwater
volume parenterals = injections: can be solution of different injection differentsolvents
solvents, can be emulsion, suspension emulsion
suspension
N
Advantages of parenteral administration an immediate effect can
be obtained intravenously an effect overM a longer period can be
obtained by an im. suspension injection a local effect can be
obtained (local anaesthesia) the body water and electrolyte balance
can be adjusted, administration of i.v. fluids can be life-saving 
intravenous nutrition is possible some drugs are inactivated in the
g.i. tract (e.g. insulin) but can be given parenterally some drugs
are irritant orally but can be tolerated when given intavenously
Disadvantages of parenteral administration
the actual injection is unpleasant special utensils are necessary for
administration a doctor or a nourse is necessary and aseptic
technique must be used there are various risks during use:
- allergic drug reaction - infection - pyrogenicity - particulation
- air embolism If the patient is hypersensitive or an overdose is
administered, the effects are difficulte to
reverse after administartion
5 criteria that must be met by all aprenteral solutions:

Page 62 of 67
- Sterile
- Pyrogen free
- Free in particles
- Physical/chemical stability
- Precise AI content
Small volumen: gel for injection, solution for injection,
suspension for injection, emulsion for injection, powder for
solution for injection, and solvent for solution for injection, and
solvent for suspension for injection, concéntrate for solution for
injection
Large volumen: solution for infusion, emulsion for infusion,
powder for solution for infusion, concnetrated for solution for
infusión, powder and solvent for solution for infusion, solvent for
parenteral use
General method of injection production:
- Preparation of ampouls
- Sterilizing and drying of ampouls
- Preparation of solution
- Filtration of solutionfilling
- Sealing
- Sterilizing the product
- Closure test
- Checking the quality of the injection
- Packaging the product
Injections: solution, suspension, emulsion, powders.
Air classification in the European Guide to GMP Whenever
possible, a process in which the product is sterilised in its final
container (terminal sterilisation) is chosen. Air class at least: grade
sterilization „C”(background „D” In case, if terminal sterilisation is not
usingheat possible (heat sensitive drugs), sterilisation by filtration (pore size:
possible
0.2 µm) is possible. Air class in general: grade „A”(background
sterilizebyfiltration

Page 63 of 67
B) If filtration is’nt possible either (suspensions), the preparation
must be compounded from sterile materials in a clean room of air
class „A” (background B).
• Clean room: Sterile parenteral solutions must be free of living
microorganisms, pyrogens, and visible particles. Room air
typically contains thousands of suspended particles per cubic foot,
most of which are too small to be seen with the naked eye. These
contaminants include dust, pollen, smoke, and bacteria. Reducing
the number of particles in the air improves the environment in
which sterile products are prepared. These particles can be
reduced by following several practices to maintain the sterile
compounding area. A sterile compounding area should be cleaned
daily and segregated from normal pharmacy operations, patient
specimens, nonessential equipment, and other materials that
produce particles  
The critical area can be completely protected with isolators. To
ensure, that a pharmaceutical cleanroom works correctly, it is
necessary to establish the following:  
- correct air supply rates  
- air supplies of the correct quality  
- minimal movement of contamination from a less clean to a
cleaner room  
- ventilation is sufficient to all parts of the cleanroom  
- concentration of airborn contaminants  
b) advantages and drawbacks of plastic packaging materials:

Advantages:
- Low weight
- Cheap
Disadvantages:
- Permeation to gases and fumes
- Adsorption/absorption
- Chemical interactions

Page 64 of 67
- Extractable substances
29.
a) Manufacturing and quality. Nondestructive test, PAT.
Conditions system of drug manufacturing. GMP. Validation.
Quality by design
The requirements of GMP, aintained with: qualified personnel with appropriate
training; adequate premises; areas of required cleanliness; suitable production
equipment; designed for easy cleaning and sterilization (CIP, SIP); validated
procedures for all production steps
Production plant areas: area for production and distribution of water for injection;
aseptic preparation area; washing area for containers, equipment and accessories;
weighing area; solution manufacturing area; area with freeze drying technology;
filling/sealing; terminal sterilization area; packaging area; IPC labour; surrounding
areas. All these areas fits to the required grade of cleanliness.
The production process of sterile products should suit to special requirements in order
to: Minimize risks of microbiological contamination Minimize risk of particulate and
pyrogen contamination Must strictly follow carefully established and validated
methods of preparation and procedure. Quality assurance is particularly important,
and the efficiency of activities much depends on the skill, training and attitudes of the
personnel involved
b)Comparison of film-coasting and traditional sugar coating:
thick
toothdecay
diabetesx
cheap
longprocess

Page 65 of 67
Colortaste
Modifiedrelease
30.
a) Veterinary preparations, technological aspects:
Veterinary preparations:
- Intravaginal dosage forms
- Topical preparations
- Insecticidal collars, ear tags, strips
- Ophtalmic preparations
- Parenteral products
- Injections
- Implants
Veterinarians need to be aware of the ability of pharmacists to
improve the dosage form, the devices that may ease administration
of the drug, or alternative dosage routes and forms attainable
through the compounding pharmacist
Dosage forms: Ideal dosage form for a pet would be one that they
love to consume. Considerations: taste, texture, color, animal
specific needs.
Challenges: Different pK and pD, different drugs availability,
drugs not available in dosages for animals, drugs discontinued,
administration problems.
Conclusions:
Patient/animal specific characteristics need to be assessed to
ensure medication administration.
Veterinary therapy can be improved by drug delivery

Page 66 of 67
Many aspects of veterinary pharmacy are analogous to main-
stream human oriented pharmacy, though of course major
pharmacological differences occur between animal species and
must be taken into account. Pharmacists are in a key position to
act as a link between pets and owners, and other health
professionals as appropriate.
Some areas in which the pharmacist can contribute include:

- Animal contact and public health 
- Routine prophylactic treatment of internal and external
parasites
- Advice on improving hygiene and issues about zoonoses 
- Guidance on dosage and administration 
- Information on welfare issues and travel
b) Accelerated and real time stability test:
Real time stability studies: Series of experiments to study the
physical, chemical, biological, biopharmaceutical and
microbiological properties of drugs during and after the shelf life
under expected storage conditions. The results are use the
determine the shelf life and the storage conditions and to prove the
correctness of planned shelf life.
Accelerated stability test: The changes during extreme storage
conditions occurs faster. The data obtained this way together with
real time stability studies can be used to determine the long term
changes. It also can be used to determine what happens in short
term extreme conditions (e.g. shipping). The accelerated stability
test not always predict the physical changes accurately

Page 67 of 67
LIST C
1.- Elix. thymi comp. Ph.Hg.VII
Aromatic tincture, orange peal tincture, thyme tincture,

33.3% NaBr solution, sucrose, H2O The volatile oil
content of thyme as mainly an expectorant action The
NaBr content has sedative effect Filtration with suction,
but before metal screen plate is placed under the filter
paper. The preparation should be of a dark brown color,
with a characteristic fragrant odor, sweat and saline taste,
clear and containing no sedimentation
2.- Suppositorium antipyreticum pro infant (Fo.No.

VII)
For 1000 pieces of suppositories:
Aminophenazonum g75.0
Adeps solidus compositus q.s.
Its antipyretic and antiinflamatory. Made by melting (2 g

per each suppository_ 2x1000= 2000g) of ademps solidus
and then add the AI and then pour into the mould which
has to be first covered by paraffin oil.
3.- suppositorium antipyreticum pro infante: (Fo. No.

VII)
For 6 suppositories:
Aminophenazonum g 0.45
Adeps solidus compositus: q.s.
Its atypiretic and antiinflamatory. Made by melting (2 g
per each suppository_ 2x6= 12g) of ademps solidus and
then add the AI and then pour into the mould which has to
be first covered by paraffin oil.
4.- Solutio iodi alcoholica(Fo. No VII)
Kalii iodidum g40.0

Aqua purificata g100.0
Iodum g50.0
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Ethanolum 96% g810.0
Iodine Tincture contains iodine which is an antiseptic. It is

for use on minor wounds, cuts and scrapes.
5.- Hydrogelum antiphlogisticum FoNo VII
Hydrophilic gels : are preparation whose the bases usually

consist of water, glycerol or propylen gligol, gelled with
suitable gelling agents such as
• tragacanth
• starch
• cellulose derivatives
• carboxyvinyl polymers
• magnesium aluminium silicates
Composition
• Hydrgeli carbomerae
• Ethanoli 96%
• Aluminii Acetici Tartarici solutionAquae purificatae
• MDS Hydrogelum for external use
Preparation
• The gel is weighted and place into a mortar
• the liquid components are mixed and stirred
• finally the jelly is completed with distilled water
• antiinflammatory effective
6.-Supp. heamorrhoidale
1. Ephedrinium chloratum, lidocainum, bismuthum subgallicum, zincum oxydatum,

acidum silicicum collidale hydrophylum
2. Adeps solidus 50 (suppository base)
3. Balsamum peruvianum
4. Oleum ricini
The components in group 1 are homogenized, then 2 is melted and 1 is suspended in 2.

After the 3 component is melted, solid fat is added.
The homogenous mass is poured into the mould.
Anesthetic effect, suspension type
7.-Sirupus sorbiti
Sorbitum

Page 2 of 4
solutio conservns
aqua dist.
The sorbitum is dissolved in dist. water, by heating. After cooling, the solution
conservans is added, and the syrup is completed up to the prescribed vol, and then
filtered.
8.-Pasta contra solarem FoNo VII.
Zinci oxidi
Titanii dioxidi
Alcoholis cetylici et stearylicy
Paraffini liquidi
MDS pastae
Preparation
the zinc oxyde and titane dioxide are homogenized and it
is suspended with previously melted mixture (alcohol and
paraffinum).
Finally the mixture is stirred until cold.
9.- Mixtura pectoralis (Fo.No VII)

Ephedrinium chloratum, ticntura ipecacuanhae, elixirium
thyme compositum, solution conservans, aqua destillata
Used for respiratory disease, expectoration
10.-Unguentum emulsificans anionicum (Fo.No VII)
- Measure and screen solid

- Heat ointment base for soften in mixer
- Add solid/powder to molten base
- Mix until cooling
- Passing through roller mill for homogeneity
Use for atopic eczema.
11.- Detergens sulfaratum (Fo.No VII)
Natrium larysulfuricum, glycerinum, alcoholum

cetylstearylicum, xanthine gummi, sulfur praecipitatum.

Page 3 of 4
Use as a disinfectant.
12.- Solvens viscosa pro oculoguttis (FoNo VII)
Hydroxyethylcellulosum, natrium chloratum,

thiomersalum solutum 0.1%, cetrimidum, aquae destillata.
Used to avoid the growth of bacteria and fungus
13.- Hydrogelum carbomerae
Carbomera, natrium hydroxydatum, solution conservantis,

aqua destillata
Used in wet cutaneous wounds and/or which produce

pruritus.
14.- Pulvis combinatus (FoNo VII)
Coffeinum, noraminophenazonum natricum mesylicum,

acidum acetylsalicylicum, acidum silicum colloidale
hydrophylum.
Used as analgesic and antipyretic

Page 4 of 4
TABLE “D”
Medicinal products as modern dosage forms in the

pharmacy
Modern dosage forms are preparation

specifically designed to improve adherence to
treatment with medications by reducing
side effects and simplifying dosing regimens.
This improved adherence can provide both
clinical and economic value by improving
treatment outcomes and reducing the use of
medical service.
Modern dosage forms offer meaningful
therapeutic advantages that may be especially important in children and the elderly who
are often sensitive to adverse effects or must adhere to complex medication regimens.
Technology advancement results in dosage technology:
• sustained-release - avoids need to take drug during other activities (school, work)
• transdermal patch - avoids dependence
• melting tablets - no need to locate water source (immediate administration)
• long-lasting injections under skin or into muscle - long-therm therapy, fewer
doctors visits
• chewable tablets - easier to swallow
• fixed-dose combinations - can save money
• inhaled insulin - avoids injections
Therapeutic advantage
• reduction in drug plasma level fluctuations, improved bioavability

• reduction in adverse side effects - drug plasma levels are mantained within narrow
window - no sharp peak, reduction in drug toxicity.
• patient comfort and compilance - oral drug delivery is the most common and
convenient for patients, reduction in frequency of drug administration
• reduction in healtcare cost - due to the reduction of side effects
Mirtazaten Qtab:
The tablet begins to disintegrate rapidly when it comes
into contact with the saliva in the mouth and can be
swallowed with or without water. The mouth should be
empty before placing the tablet on the tongue. The tablet
should not be broken or chewed.
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Orodispersible tablets are fragile, therefore you should not
push the tablet through the foil as this may cause damage.
Open the blister pack by: - holding the blister pack by the
edges and tearing off one section along the perforation,
- lifting the foil at the marked spot and peeling it off
carefully, -tipping the tablet out. Place the tablet on the
tongue immediately after removing it from its blister pack.
Aspirin Effect orodisperse
Analgesic, antinflammatory, antipyretic effects.

It does not need to be taken with water because the granules dissolve directly on the
tongue.
Eccipienti
citrato monosodico, sodio idrogeno carbonato, acido citrico anidro, mannitolo
acido ascorbico.
Adalat gits oros tablet
Tablet core
Polyethylene oxide (swelling hydrocolloid polymers)
Hypromellose
Magnesium stearate
NaCl (osmotic agent)
Ferric oxide (colorant)
Coating
Cellulose acetate (semipermeable membrane former)
Macrogol
Hydroxyproprylcellulose
Hypromellose
Propylene glycol
2+
API : Nifedipine (Ca channel inhibitor)
Therapy: is used for the treatment of all grades of hypertension and for the chronic
angina pectoris, either as monotherapy or in combination with B-Blocker
OROS (Osmotic [Controlled] Release Oral [Delivery]

System)
Is an advanced controlled release oral drug delivery
system in the form of a rigid tablet with a semi-
permeable outer membrane and one or more small laser
drilled holes in it. As the tablet passes through the body,
water is absorbed through the semipermeable membrane
via osmosis, and the resulting osmotic pressure is used to
push the active drug through the opening(s) in the tablet.

Page 2 of 5
OROS is a trademarked name owned by ALZA
Corporation, which pioneered the use of osmotic pumps
for oral drug delivery.
The development of an additional internal "push layer" comprised of material (a

swellable polymer) that would expand as it absorbed water, which then pushed the
drug layer (which incorporates a viscous polymer for suspension of poorly soluble
drugs) out of the exit hole at a controlled rate.[1][4] Osmotic agents such as sodium
chloride, potassium chloride, or xylitol are added to both the drug and push layers to
increase the osmotic pressure.
Cardura XI osmotic tablet

(KLACID)
This tablet should be swallowed whole

Patients should not chew, divide or
crush the tablets.
In this tablet the API is sourrounded by

an inert, non absorbable shell that has
been specially designed to control the
release of the drug over a prolonged period.
After transit the GI, the empty tablet shell is exctreted.
API: Doxazosin mesylate, a quinazoline, is an α1-selective alpha blocker used to treat

high blood pressure and urinary retention associated with benign prostatic hyperplasia
(BPH).
Patients should be informed that Cardura XL tablets
should be swallowed whole. Patients should not chew,
divide or crush the tablets.
In Cardura XL, the active compound is surrounded by an
inert, non-absorbable shell that has been specially
designed to control the release of the drug over a
prolonged period. After transit through the gastrointestinal
tract, the empty tablet shell is excreted. Patients should be
advised that they should not be concerned if they
occasionally observe remains in their stools that look like
a tablet.
Adults: the usual recommended dosage of Klacid LA in adults is one 500 mg
modified-released tablet daily to be taken with food. In more severte infections, the
dosage can be increased to two 500mg modified release tablets taken as one dose
daily. Tablets myst be swallowed whole.

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Retard clarithromycin
Film coated tablet, retarded released
API : macrolides, Clarithromycin, sold under the brand name Biaxin, is an antibiotic
used to treat various bacterial infections. This includes strep throat, pneumonia, skin
infections, H. pylori infection, and Lyme disease, among others.
Excipients : sodium alginate, polymer that can retard the release of the drug.
Ralnea XL
Prolonged release tablet
API: ropinirole, which belongs to a group of medicines called dopamine agonists.
Therapy: Treatment of Parkinson's disease under

the following conditions:
• Initial treatment as monotherapy, in order to delay the introduction of levodopa

• In combination with levodopa, over the course of the disease, when the effect of
levodopa wears off or becomes inconsistent and fluctuations in the therapeutic effect
occur ("end of dose" or "on-off" type fluctuations)
Betalok ZOK
API: Metoprolol, b-bloker
Tablet containing pellets, can be helded.

Zero order kinetics (the reaction is independent of the concentration)
Long action
Prolong release with constant rate
Madopar HBS
Gastroretention : Floating capsule
API: levodopa and benserazide. Treatment of Parkinson's desease.
Mechanism : Low density system that can float over the gastric contents without
affecting the gastric emptying rate for a prolonged period of time.
The gastric emptying time can result in incomplete drug release from the drug delivery
system, leading to reduced efficacy of administered dose.
Factors affecting floating time
Density, size and shape of dosage form

Single and multiple unit formulation
Nature of meal
Age and gender
Frequency of feed
Advantages

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• Enhanced bioavailability
• Sustained drug delivery / reduced frequency of dosing
• Reduced fluctuations of drug concentration
• Reduced counter activity of the body
Disadvantage
• Drug unstable in the acidic medium

• High level of fluid in the stomach is required to work efficiently
• Not suitable for drugs that have solubility or stability problem in GIT
Supradyn sugar coated vitamin tablets
Slow manufacturing process due to many steps of sugar coating
Dry powder Inhaler (Seebri breezhaler)
Drug in hard capsules with moisture restant in the packaging.

Page 5 of 5

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Pharmaceutical technology IV

Semisolid dosage forms: Ointments, pastes, gels creams,

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Surfactants may act as :

Surfactants are usually organic compounds that are amphiphilic,

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- Conventional-release dosage forms: Are preparations showing a release of active substances

b) Study of filtration process:

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Requirements for pharmaceutical preparations:

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Test ofointmentandsuppositorybasematerials Itestrateofabsorption

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To provide evidence how the drug substance or drug product

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b) Comparison of dry and wet milling processes: inpharmaindustry wetmining후

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Demands: Protection (stability test conditions), compatibility,

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Critical manufacturing paramenter is a process paramenter that

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Rheology is the study of flow behaviors of liquids. In pharmacy,

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One of the method of measuring Newtonian visocity is with an

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3. Dilatant Rheogram: The last non-Newtonian flow behavior is

b) Test of membrane filters:

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b) Isotinizing setting and calculations:

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L - molal freezing point depression of the solute

The compounds have been grouped according to their L-values.

E = (L×MNaCl)/(M×LNaCl) = (L×58×45)/(M×3×4) = 17 (L/M)

M - molecular mass of the compound

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Pharmaceutical equivalence: Medicinal products are

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Process steps are:

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They are prepared by:

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Enantiotropic: reversible transition between polymorphic forms

Monotropic: irreversible, transition from metastable to stable form, unidirectionally.

Detection of different polymorphic forms: by X-ray diffraction and IR adsorption.

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b)Controlled area and clean area in the manufacture:

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The preparation is essentially similar to that for a mono disperse

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The most efficient method of producing fine particles is by dry

4. Easy to control: physical form; particle size; dose  

5. Clean process; require no wash-up  

Basic requirement is the chemical purity of the active agent. 