Manufacturing Considerations in Liquids

 Equipment
 Packaging labeling and storage
A- Equipment:
In general, the type of equipment used in the manufacture of oral solutions consists of:
1. Mixing tanks equipped with agitators
2. Measuring and weighing devices for:
 large
 small amounts of solids and liquids

3-Filtration system for the

 final polishing
 sterilization of the solution

-All equipment must be : cleaned and sanitized before use.

-dilute solutions of hydrogen peroxide phenol derivatives, and peracetic acid.

- alcohol, boiling water autoclaving, steam, or dry heat.

1) The mixing tanks

 used for compounding ( large scale) .
 constructed of polished stainless steel
- ss 3144
- ss 316
 jacketed to allow for heating or cooling of the contents.
 covered equipped with the see-through charging ports and illumination
for easy observation of the contents.
- Equipped with built-in agitation system.
 After compounding the liquid is :
- clarified by cycling through a filtration system.
- the polished solution is stored in an adjacent tank until released .
 the release, of this liquid may be transported, either manually:
- transport tanks
- by pumping (or by gravity flow) through a suitable liquid delivery
conduit.

A major source of microbial contamination :

- Water condensate ......................

- Steam ..................

2) Measuring devices
- large and small , solids and liquids , cylinders big and small pipets and
balances.
3) Filtration System: Filtration is a unit operation in which a mixture of liquid and solids. slurry or feed
is forced through a porous medium in which the solids form a cake on the surface and the clear liquid
(filtrate is discharged from the filter)

Objective in filtration :

 - sparkling liquid free from amorpkous or crystalline

preciphates, colloidal hazes or insoluble liquid droplets.
 - the filter medium is the surface upon which the solids
are deposited on the filter.

These filter media are as follows:

(1) Filter cloth

-is woven from synthetic fiber, natural fiber or metal.

- Examples: stainless wire cloth, cotton cloth and nylon.

- Filter cloth is used to strain simple syrup or syrup preparations.

- Nylon is often superior for pharmaceutical use

(2) non-woven filter media :includess felt, bonded fabrics and kraft papers.

A felt:

- fibrous mass free from bonding agents

- mechanically interlocked to yield specific pore diameters that have controlled particle retention.

- recommended for gelatinous solutions or with fine particular matter ( aluminium hydroxide gel)

A bonded fabric:

-is made by binding textile fabrics with resins, solvents and plasticizers.

-These are not widely accepted due to interaction with additives

Kraft paper :

-is used as pharmaceutical standard.

- offers controlled porosity, limited absorption capacity and a low cost.

- all pressure filters and the most widely used in commercial scale: sol-called plate and frame filter
press is the simplest .

(3) Membrane filter media

- basic tools for microfiltration

- used particularly in preparation of sterile solutions.

- made of various esters of cellulose or from nylon, teflon, polyvinyl chloride or silver.

(4) Filter aids

- special type of filter media.

- act by forming a highly porous and non- compressible cake which retains solids

- forms a fine surface deposit that screens out all solids.

Examples are diatomite (diatomaceous earth, infusorial earth. kiesulghur, celite, super gel)

WHY PREFERRED? inert and insoluble.

Cellulose and asbestos are used in limited application soluble. ( high cost )

- The most important factor for filter aid is inertness.

-Filtration efficiency may be affected by changes in temperature.

Large-scale filter set-ups:

(1) Vacuum type-like pump

(2) Plates of porous stoneware

(3) Rotary vacuum filters.

Types of filter presses:

1. Parallel filtration-series of filters and liquid passes only through one disk at a time.
used for faster or increased rate of filtration .
2. Series filtration liquid goes through all the filter disks in a series.
recommended for parenteral products.

Compounding Procedure
 Difference between diluted and concentrated solution

1-Dilute solutions, prepared by charging the solute to the solvent and agitating until the
solution is homogenous.
2- concentrated solutions
advantageous to employ heat to facilitate the solution of sucrose , (This step calls for the 2
Yaview solution of sucrose .
- rapidly soluble even in cold water.
- Menthol flavor are dissolved in an aliquot of the alcohol and this alcoholic solution is
charged to the batch.
- Solutes present in small concentrations.
- dyes and other intensely colored materials
- should be pre-dissolved prior to mixing with the main portion of the batch.

Raw Materials:
- should conform to well thought out Specifications.
- assure identity, purity, uniformity, and freedom from excessive microbial contamination
- Incoming raw materials should be impounded and thoroughly tested before they are
released for manufacturing.
- water is usually the most important constituent in a liquid product. It should meet the USP
requirements for puied water. It may be obtained by distillation or ion-exchange treatment(
reverse osmosis) .
 TREATMENT EMPLOYED TO UPGRADE MICROBIAL PURITY OF H2O
a. Reverse osmosis purification
b. Ultraviolet sterilisation
c. Membrane filtration
d. Constant circulation in piping systems

# UV sterilization

The use of ultraviolet sterilization :

(a) The flow rate of the water should not exceed the capability of the sterilizing unit.

(b) Even if sterility is achieved, a filter should still be used downstream to remove the dead
microorganism and particulate matter.

Containers

Cleaning cycle in new and unused container

1. Air-jet to remove dust or other loose particles

2. shock treatment.
3. Rinse with hot distilled water
4. Air-jet again to remove particles of water.

Cleaning cycle for used containers:

1. Several pre-rinse with ordinary water under pressure.

2. Several (10) hot detergents (180°C) treatment.
3. Four preliminary rinses with hot water under pressure.
4. Several more rinses of hot water not under pressure.
5. Rinse with Distilled water .
6. Hot air-jet for 5 minutes.

Clarification separation of colloidal as well as solid materials from liquids without the use of filters.
used for very fine, amorphous or colloidal solids that will clog the filters.( Al hydroxide gel)( graving)

Methods may be used for thermostable preparation). Heating reduces viscosity and causes
suspended particles to subside. of Clarification:

1. Gravitational or gradual sedimentation (simplest) or aging process. (Decantation)

2. Heating

3 Adding clarifiers that will absorb contam

Aging involves keeping the liquid preparation in storage tanks for a period of time.

purposes

 to give various ingredients time to blend with one another .

 also to allow gradual sedimentation when two solvents are mixed .
Causes of gradual sedimentation:

(a) Gradual decomposition

(b) Chemical reaction

(c) Incompatibilities

(d) Faulty filtration

(e) Bacterial growth

(f) Insufficient aging

B. Packaging, Labeling and Storage

1. Packaging:

Filling of Liquids: depending on the:

a) Characteristics of the liquid.

b) Type of package into which the liquid is placed.
c) Required production output .

Three Basic Filling Methods:

1. Gravimetric

2. Volumetric

3. Constant level

I. gravimetric filling:
- is filling containers to a given weight.
- generally limited to large container or to highly viscose products
- does not readily lend itself to high speed automatic equipment.
II. Volumetric filling
- usually accomplished by positive displacement piston action.
- fill amount is measured by the stroke of the piston that in all machines is varied to d
limited degree. Major changes in fill amount needs changing the piston and cylinder
assembly.
- can also be accomplished by pumping of a liquid at a constant pressured through an
orifice of constant size for a pre-determined period of time.

Several significant problems associated with volume filling are:

(a) Highly viscous ,cause the pistons to seize, (resulting in either loss of fill accuracy or line
breakdown).
(b) thin liquids :
- may flow past the piston:
*causing uncontrollable dripping from the filling spout
*fill inaccuracies.
(c) containers are used that are not dimensionally uniform. (the fill height varies)
 i. Constant leve filling:
- uses the container as the means for controlling the fill amount of each unit.
- use of siphon:
* The oldest form of constant-level filler
* slow and is rarely used when high production rates are required.

THREE CATEGORIES OF FILLING:

1. Vacuum filling
2. Gravity-vacuum filling
3. Pressure-vacuum filling

Vacuum filling –

- a seal must be made between the filling head and the container.

- vacuum is then developed within the container, which causes the liquid to flow from the bulk
liquid tank to the container.

Gravity-vacuum filling

- the bulk liquid tanks are a level above the filling stem.

- the driving force for liquid flow results from both the negative pressure in the container and the
force of gravity.

pressure-vacuunl filling

-positive pressure is applied to the bulk liquid, which in combination with the vacuum developed in
the container.

- allows for rapid filling of even highly viscous liquids

EXCESSIVE FOAM

A common problem to all types of liquid filling machines, particularly bothersome with high- speed
automatic equipment, is excessive foam. Foaming during the filling operation often can be
decreased by:

(a) Filling equipment that minimizes product turbulence

(b) Closed-system filling

(c) Mechanical defoaming devices

(d) Reduction in the speed of the filling line.

2. LABELING:
Drug Labeling includes not only the labels,placed, on the immediate container and
packaging.
- these include:
1. Package inserts accompanying / drug literature.
2. Advertising
3. Promotional materials to the drug product
 The label of legend / ethical drugs contain the following information:
(1) Nonproprietary name of the drug and the trademark name if one is used.
(2) The name and address of the manufacturer or distributor .
(3) quantitative statement of the amount of drug presents per unit of weight, volume, or
dosage unit .
(4) dosage form .
(5) net amount of drug product contained in the package.
(6) "Caution- Food, Drug and Cosmetic Act prohibits dispensing without a prescription" .
(7) usual dose of the product , special dosage guidelines for children or for other patients.
(8) A label reference
(9) Special storage instruction .
(10) Drug registration number from the BFAD
(11) Manufacturer's control number identifying the batch or lot of the drug.
(12) Expiry date
(13) The warning "May be habit forming" for controlled drugs.
(14) The symbol Rx .

OTC MEDICATIONS INFORMATION

1. Statements of all conditions.
2. dose for drug
3. Frequency of administration
4 Maximum duration of administration or application prior to consulting a physician.
5. Time of administration
6. Route of administration .
7. Preparation for use .
8. Warnings

3-STORAGE

-Proper storage to insure the stability for the period of its intended shelf-life.

- no specific storage or limitations are provided,( storage conditions include protection from
moisture, freezing, and excessive heat).

HETEROGENEOUS LIQUID PREPARATIONS:

- Emulsions and suspensions .

Reasons for formulating drugs in forms in which the drug is not in the molecular state:

1. Improved stability

2. Improved taste

3. Low water solubility

4. Palatability

5 Ease of administration
Pharmaceutical Suspensions

- coarse dispersion ...............

- consist of :

1) The continuous or external phase, liquid or semisolid.

2) dispersed or internal phase is made up of particulate matter , insoluble.

3 major concerns:

- ensure adequate dispersion in vehicle.

- minimize settling

- prevent caking

A STATIONARY SUSPENSION: must remain sufficiently homogeneous for at least the period of time
necessary to remove and administer the required dose after shaking its container.

THEORETICAL CONSIDERATIONS IN THE MANUFACTURE OF PHARMACEUTICAL SUSPENSIONS

a) Wetting/ wettability property:

b) Particle interactions and behavior
c) Sedimentation rate

a)Wetting/ Wettability Property:

Frequently encountered difficulty in suspension formulation .

HOW ARE SOLIDS WETTED?

When a strong affinity exists between a liquid and a solid the liquid easily forms a film over the
surface of the solid.

WHY SOME SOLD NOT WETTED EASILY?

WHEN affinity is nonexistent or weak :

- the liquid has difficulty displacing the air or other substances surrounding the solid.

-there exists an angel of contact between the liquid and the solid.

WHAT CAUSES THIS TENSIONS?

Caused by unbalanced intermolecular forces in the various phases similar to the familiar analogous
phenomenon of the convex “skin” formation over the surface of a glass of water filled to the brim.

Terms In Aqueous Suspensions:

a) hydrophilic:

- easily wet by water or other polar liquids.

- increase the viscosity of water suspensions.

b) hydrophobic:

- Repel water.

- can be wetted by nonpolar liquids

- do not alter the viscosity of aqueous dispersions.

USE OF SURFACTANT

1) Helpful for modifying the Wetting characteristics of powders.

2) Decrease the solid liquid interfacial tension

MECHANISM OF SURFACTANT ACTION:

Involve adsorption of the hydrocarbon chain by hydrophobic surface , with the polar moiety of the
surfactant being then directed towards the aqueous phase.

MATERIALS THAT CAN BE USED TO AID DISPERSION OF HYDROPHOBIC SOLIDS :

1) Hydrophilic polymers:
- sodium carboxymethylcellulose

2). Water insoluble hydrophilic materials:

- such as bentonite , aluminium magnesium silicates

-colloidal silic

* IF POOR WETTING USE : LANOLIN DERIVATIVES

TWO TECHNIQUES DEVELOPED BY THE PAINT INDUSTRY THAT COULD BE APPLIED

PHARMACEUTICALLY

- involve determining the so-called wet and flow points.

- wet point:

- measure the amount of vehicle needed to just wet all of the powder.

- involve incorporation of the additive in the powder by rubbing ...........

- flow point :

-measure the amount of vehicle needed to produce pourability

-............................. beaker

- a low wet point coupled with a low flow point , indicates a good deaggregation or dispersion.

b) PARTICLE INTERACTIONS AND BEHAVIOUR

Lyophobic Vs lyophilic

Synonyms with non wetting and Wetting respectively

- difference between is their sensitivity to the presence of electrolyte.

Lyophobic: are sensitive to the addition of salts ( it will ppt)

Lyophilic are not

Lyophilic readily wet by water, large amounts of electrolyte may affect the solution by salting out
effects.

Electrolyte: problem...................... agents .

Act by reducing....... particles.

Allows the particles to form loos Flocs ....... suspension

Particle interaction: the ability of particles to come together and form floc depend on their surface.

Change zeta....................

Particle interaction:

- can have significant effect on suspension stability.

- inter ..........

- suspension with high solid...............

TERMS USED TO DESCRIBE AGGREGATION PHENOMENA:

1) FLOCCULE/ OPEN NETWORK AGGREGATE:

- characterized by a fibrous , fluffy open network of aggregated particles.
- rigid surfactant aggregates settle quickly to form a high sediment.
- easily redispersable

2) COAGULATE / CLOSED AGGREGATE:

- characterized by tight packing produced by surface film bonding

- aggregates settle slowly

- low sediment heights

- not easily redispersed

- upon sedimentation, the aggregate tend to form a single large “film

Bonded” Aggregate, which is difficult if not impossible to redispersed.

2) DEAGGREGATED OR DISPERSED FORM :

- individual particles are dispersed as discrete entities.
- slowly settle
-attain the lowest height
- possess a high potential for caking

Sedimentation and aggregation rates , properties of suspension systems governed by

particle size, particle-particle interactions, densities of the particles and the medium, and the
viscosity of the continuous phase .
SUBSIDENCE

- term often used to describe the settling of an aggregated system .

- refers to the settling rate or descending of the boundary between the sediment and the clear
supernatant above it.

Polydispersed system

- those having many different particle sizes present.

- the large particles settle down more rapidly than the smaller particles.

TWO TYPES OF SUSPENSION SYSTEMS:

1. Flocculated/ aggregated suspension system:

- particles are linked together into flocs or appear as floccules or like stuffs of wool with a
loose fibrous structure.
- When such a system settles, two distinct layers form
- called coagulated or colloidally unstable system.
- appear to be coarse

2. Deflocculated system:

- the particles settle as a dense sediment.

- results in pharmaceutically poor suspension.

IDEAL SUSPENSION:

- must be redispersabl with mild agitation.

- insure dosage uniformity

- tendancy of particles............ them.

differential manometer :

can be used to compare the pressure of a suspension near its bottom and top in a container.

- aggregated suspension shows the same pressure at both points. .

- A deaggregated suspension, however, exerts more pressure near its bottom.

Caking: is defined as the formation of a nondispersible sediment within a suspension system.

MAJOR CAUSES OF CAKING:

1. Crystal Bridging - particle surface crystal growth occurs on two or more particles simultaneously
- results in the steady formation of crystal-linked particles .

- leading to the formation of a highly linked sediment akin to concrete or plaster .

- in temperature that occur during shelf storage lead to unexpectedly rapid caking via crystal
bridging.

- Ostwald ripening, is unavoidable.

- minimized by utilizing the open network aggregated (floccule) suspension type, as the particles
cannot sediment to a close proximity because of the rigidity of the aggregate.

2. CLOSED AGGREGATE (COAGULE) FORMATION:

A sedimented, highly coagulated suspension tends to form large coagules as the surface
films present on coagulated particles cause the "filmed" particles to cling to each other.

c) Sedimentation Rate:

Stokes relation/stock law describes the sedimentation velocity of a particle in suspension.

-makes is clear that pharmaceutical suspensions are destined to settle.

- particle diameter or radius, as it is a squared term, as technologists, the formulators are most able
to control this and the viscosity of the medium.

-as the solids content is increased, viscosity also is increased.